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Desidustat

July 9, 2020 4:52 am / Leave a comment

Ranjit Desai

Inventor of Oxemia (Desidustat), a breakthrough PHD inhibitor approved for Chronic Kidney Diseases (CKD) / Accomplished pharma executive / 4 INDs in 4 years, ZYDUS LIFESCIENCES

DESIDUSTAT

Formal Name

N-[[1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl]carbonyl]-glycine

CAS Number 1616690-16-4

Molecular Formula C₁₆H₁₆N₂O₆

Formula Weight 332.3

FormulationA crystalline solid

λ_max233, 291, 335

2-(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid

desidustat

Glycine, N-((1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl)carbonyl)-

N-(1-(Cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine

ZYAN1 compound

(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Desidustat | C16H16N2O6 - PubChem

Oxemia (Desidustat) has received approval from the Drug Controller General of India. This was an incredible team effort by Zydans across the organization and I am so proud of what we have accomplished. Oxemia is a breakthrough treatment for Anemia associated with Chronic Kidney Disease in Patients either on Dialysis or Not on Dialysis, and will help improve quality of life for CKD patients. Team #zydus , on to our next effort!

Desidustat (INN, also known as ZYAN1) is a drug for the treatment of anemia of chronic kidney disease. This drug with the brand name Oxemia is discovered and developed by Zydus Life Sciences.^[1] The subject expert committee of CDSCO has recommended the grant of permission for manufacturing and marketing of Desidustat 25 mg and 50 mg tablets in India,based on some conditions related to package insert, phase 4 protocols, prescription details, and GCP.^[2] Clinical trials on desidustat have been done in India and Australia.^[3] In a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study, a mean hemoglobin increase of 1.57, 2.22, and 2.92 g/dL in desidustat 100, 150, and 200 mg arms, respectively, was observed.^[4] The Phase 3 clinical trials were conducted at additional lower doses as of 2019.^[5] Desidustat is developed for the treatment of anemia as an oral tablet, where currently injections of erythropoietin and its analogues are drugs of choice. Desidustat is a HIF prolyl-hydroxylase inhibitor. In preclinical studies, effects of desidustat was assessed in normal and nephrectomized rats, and in chemotherapy-induced anemia. Desidustat demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization.^[6]^[7] Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation.^[8] In January 2020, Zydus entered into licensing agreement with China Medical System (CMS) Holdings for development and commercialization of desidustat in Greater China. Under the license agreement, CMS will pay Zydus an initial upfront payment, regulatory milestones, sales milestones and royalties on net sales of the product. CMS will be responsible for development, registration and commercialization of desidustat in Greater China.^[9] It has been observed that desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress ^[10] A clinical trial to evaluate the efficacy and safety of desidustat tablet for the management of Covid-19 patients is ongoing in Mexico, wherein desidustat has shown to prevent acute respiratory distress syndrome (ARDS) by inhibiting IL-6.^[11] Zydus has also received approval from the US FDA to initiate clinical trials of desidustat in chemotherapy Induced anemia (CIA).^[12]. Desidustat has met the primary endpoints in the phase 3 clinical trials and Zydus had filed the New Drug Application (NDA) to DCGI in November, 2021.^[13]\

CLIP

https://www.businesstoday.in/industry/pharma/story/zydus-receives-dcgi-approval-for-new-drug-oxemia-what-you-need-to-know-324966-2022-03-07

Zydus receives DCGI approval for new drug Oxemia; what you need to know

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, Zydus said in a statement.

Gujarat-based pharma company Zydus Lifesciences on Monday received the Drugs Controller General of India (DCGI) approval for its new drug application for a first-of-its-kind oral treatment for anemia associated with Chronic Kidney Disease (CKD) – Oxemia (Desidustat).

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, the drug firm said in a statement.

Desidustat showed good safety profile, improved iron mobilization and LDL-C reduction in CKD patients in DREAM-D and DREAM-ND Phase III clinical trials, conducted in approximately 1,200 subjects. Desidustat provides CKD patients with an oral convenient therapeutic option for the treatment of anemia. The pharma major did not, however, declare the cost per dose if the drug is available in the market.

“After more than a decade of research and development into the science of HIF-PH inhibitors, results have demonstrated that Oxemia addresses this unmet need and additionally reduces hepcidin, inflammation and enables better iron mobilization. This advancement offers ease of convenience for the patient and will also reduce the disease burden by providing treatment at an affordable cost, thereby improving the quality of life for patients suffering from Chronic Kidney Disease,” Chairman of Zydus Lifesciences Pankaj Patel said.

Chronic Kidney Disease (CKD) is a progressive medical condition characterised by a gradual loss of kidney function and is accompanied by comorbidities like anemia, cardiovascular diseases (hypertension, heart failure and stroke), diabetes mellitus, eventually leading to kidney failure.

PATENT

US277539705

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=C922CC7937C0B6D7F987FE395E8B6F34.wapp2nB?docId=US277539705&_cid=P21-KCEB8C-83913-1

Patent applications WO 2004041818, US 20040167123, US 2004162285, US 20040097492 and US 20040087577 describes the utility of N-arylated hydroxylamines of formula (IV), which are intermediates useful for the synthesis of certain quinolone derivatives (VI) as inhibitors of hepatitis C (HCV) polymerase useful for the treatment of HCV infection. In these references, the compound of formula (IV) was prepared using Scheme 1 which involves partial reduction of nitro group and subsequent O-alkylation using sodium hydride as a base.

(MOL) (CDX)

The patent application WO 2014102818 describes the use of certain quinolone based compound of formula (I) as prolyl hydroxylase inhibitors for the treatment of anemia. Compound of formula (I) was prepared according to scheme 2 which involved partial reduction of nitro group and subsequent O-alkylation using cesium carbonate as a base.

(MOL) (CDX)

The drawback of process disclosed in WO 2014102818 (Scheme 2) is that it teaches usage of many hazardous reagents and process requires column chromatographic purification using highly flammable solvent at one of the stage and purification at multi steps during synthesis, which is not feasible for bulk production.

Scheme 3:

(MOL) (CDX)

Scheme 4.

(MOL) (CDX)

The process for the preparation of compound of formula (I-a) comprises the following steps:

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, Ethanol (1.25 L) charged at room temperature. 2-iodobenzoic acid (250 g, 1.00 mol) was added in one lot at room temperature. Sulphuric acid (197.7 g, 2.01 mol) was added carefully in to reaction mixture at 20 to 35° C. The reaction mixture was heated to 80 to 85° C. Reaction mixture was stirred for 20 hours at 80 to 85° C. After completion of reaction distilled out ethanol at below 60° C. The reaction mixture was cooled down to room temperature. Water (2.5 L) was then added carefully at 20 to 35° C. The reaction mixture was then charged with Ethyl acetate (1.25 L). After complete addition of ethyl acetate, reaction mixture turned to clear solution. At room temperature it was stirred for 5 to 10 minutes and separated aqueous layer. Aqueous layer then again extracted with ethyl acetate (1.25 L) and separated aqueous layer. Combined organic layer then washed with twice 10% sodium bicarbonate solution (2×1.25 L) and twice process water (2×1.25L) and separated aqueous layer. Organic layer then washed with 30% brine solution (2.5 L) and separated aqueous layer. Concentrated ethyl acetate in vacuo to get ethyl 2-iodobenzoate in 95% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 248.75 (M+H). ¹H NMR (CDCl ₃): 1.41-1.37 (t, 3H), 4.41-4.35 (q, 2H), 7.71-7.09 (m, 1H), 7.39-7.35 (m, 1H), 7.94-7.39 (m, 1H), 7.96-7.96 (d, 1H). HPLC Purity: 99.27%

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, toluene (1.5 L) was charged at room temperature. Copper (I) iodide (15.3 g, 0.08 mol) was added in one lot at room temperature. Glycine (39.1 g, 0.520 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Ethyl 2-iodobenzoate (221.2 g, 0.801 mol) was added in one lot at room temperature. Tert-butyl (cyclopropylmethoxy)carbamate (150 g, 0.801 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Potassium carbonate (885.8 g, 6.408 mol) and ethanol (0.9 L) were added at 25° C. to 35° C. Reaction mixture was stirred for 30 minutes. The reaction mixture was refluxed at 78 to 85° C. for 24 hours. Reaction mixture was cooled to room temperature and stirred for 30 minutes. The reaction mixture was then charged with ethyl acetate (1.5 L). After complete addition of ethyl acetate, reaction mixture turned to thick slurry. At room temperature it was stirred for 30 minutes and the solid inorganic material was filtered off through hyflow supercel bed. Inorganic solid impurity was washed with ethyl acetate (1.5 L), combined ethyl acetate layer was washed with twice water (2×1.5 L) and separated aqueous layer. Organic layer washed with 30% sodium chloride solution (1.5 L) and separated aqueous layer. Ethyl acetate was concentrated in vacuo to get ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate in 89% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 357.93 (M+Na). ¹H NMR (CDCl ₃): 0.26-0.23 (m, 2H), 0.52-0.48 (m, 2H), 1.10-1.08 (m, 1H), 1.38-1.35 (t, 3H), 1.51 (s, 9H), 3.78-3.76 (d, J=7.6 Hz, 2H), 4.35-4.30 (q, J=6.8 Hz, 2H), 7.29-7.25 (m, 1H), 7.49-7.47 (m, 2H), 7.78-7.77 (d, 1H). HPLC Purity: 88.07%

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

(MOL) (CDX)

In a 10 L fixed glass assembly, dichloromethane (2.4 L) was charged at room temperature. Ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate (200 g, 0.596 mol) was charged and cooled externally with ice-salt at 0 to 10° C. Methanolic HCl (688.3 g, 3.458 mol, 18.34% w/w) solution was added slowly drop wise, over a period of 15 minutes, while maintaining internal temperature below 10° C. Reaction mixture was warmed to 20 to 30° C., and stirred at 20 to 30° C. for 3 hours. The reaction mixture was quenched with addition of water (3.442 L). Upon completion of water addition, the reaction mixture turn out to light yellow coloured solution. At room temperature it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with Dichloromethane (0.8 L). Combined dichloromethane layer then washed with 20% sodium chloride solution (1.0 L) and separated aqueous layer. Concentrated dichloromethane vacuo to get Ethyl 2-((cyclopropylmethoxy)amino)benzoate in 92% yield, as an oil. MS (ESI-MS): m/z 235.65 (M+H) ⁺. ¹H NMR (CDCl ₃): 0.35-0.31 (m, 2H), 0.80-0.59 (m, 2H), 0.91-0.85 (m, 1H), 1.44-1.38 (t, 3H), 3.76-3.74 (d, 2H), 4.36-4.30 (q, 2H), 6.85-6.81 (t, 1H), 7.36-7.33 (d, 1H), 7.92-7.43 (m, 1H), 7.94-7.93 (d, 1H), 9.83 (s, 1H). HPLC Purity: 87.62%

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

(MOL) (CDX)

In a 2 L fixed glass assembly, Acetonitrile (0.6 L) was charged at room temperature. Ethyl 2-((cyclopropylmethoxy)amino)benzoate (120 g, 0.510 mol) was charged at room temperature. Ethyl hydrogen malonate (74.1 g, 0.561 mol) was charged at room temperature. Pyridine (161.4 g, 2.04 mol) was added carefully in to reaction mass at room temperature and cooled externally with ice-salt at 0 to 10° C. Phosphorous oxychloride (86.0 g, 0.561 mol) was added slowly drop wise, over a period of 2 hours, while maintaining internal temperature below 10° C. Reaction mixture was stirred at 0 to 10° C. for 45 minutes. The reaction mixture was quenched with addition of water (1.0 L). Upon completion of water addition, the reaction mixture turns out to dark red coloured solution. Dichloromethane (0.672 L) was charged at room temperature and it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with dichloromethane (0.672 L). Combined dichloromethane layer then washed with water (0.400 L) and 6% sodium chloride solution (0.400 L) and separated aqueous layer. Mixture of acetonitrile and dichloromethane was concentrated in vacuo to get Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate in 95% yield, as an oil. MS (ESI-MS): m/z 350.14 (M+H) ^l. ¹H NMR (DMSO-d ₆): 0.3-0.2 (m, 2H), 0.6-0.4 (m, 2H), 1.10-1.04 (m, 1H), 1.19-1.15 (t, 3H), 1.29-1.25 (t, 3H), 3.72-3.70 (d, 2H), 3.68 (s, 2H), 4.17-4.12 (q, 2H), 4.25-4.19 (q, 2H), 7.44-7.42 (d, 1H), 7.50-7.46 (t, 1H), 7.68-7.64 (m, 1H), 7.76-7.74 (d, 1H). HPLC Purity: 86.74%

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

(MOL) (CDX)

In a 10 L fixed glass assembly under Nitrogen atmosphere, Methanol (0.736 L) was charged at room temperature. Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate (160 g, 0.457 mol) was charged at room temperature. Sodium methoxide powder (34.6 g, 0.641 mol) was added portion wise, over a period of 30 minutes, while maintaining internal temperature 10 to 20° C. Reaction mixture was stirred at 10 to 20° C. for 30 minutes. The reaction mixture was quenched with addition of ˜1N aqueous hydrochloric acid solution (0.64 L) to bring pH 2, over a period of 20 minutes, while maintaining an internal temperature 10 to 30° C. Upon completion of aqueous hydrochloric acid solution addition, the reaction mixture turned to light yellow coloured slurry. Diluted the reaction mass with water (3.02 L) and it was stirred for another 1 hour. Solid material was filtered off and washed twice with water (2×0.24 L). Dried the compound in fan dryer at temperature 50 to 55° C. for 6 hours to get crude ethyl 1-(cyclopropylmetboxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a solid.

Purification

In a 10 L fixed glass assembly, DMF (0.48 L) was charged at room temperature. Crude ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (120 g) was charged at room temperature. Upon completion of addition of crude compound, clear reaction mass observed. Reaction mixture stirred for 30 minutes at room temperature. Precipitate the product by addition of water (4.8 L), over a period of 30 minutes, while maintaining an internal temperature 25 to 45° C. Upon completion of addition of water, the reaction mixture turned to light yellow colored slurry. Reaction mixture was stirred at 25 to 45° C. for 30 minutes. Solid material was filtered off and washed with water (0.169 L). Dried the product in fan dryer at temperature 50 to 55° C. for 6 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 81% yield, as a solid. MS (ESI-MS): m/z 303.90 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.37-0.35 (m, 2H), 0.59-0.55 (m, 2H), 1.25-1.20 (m, 1H), 1.32-1.29 (t, 3H), 3.97-3.95 (d, 2H), 4.36-4.31 (q, 2H), 7.35-7.31 (in, 1H), 7.62-7.60 (dd, 1H), 7.81-7.77 (m, 1H), 8.06-7.04 (dd, 1H). HPLC Purity: 95.52%

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, tetrahydrofuran (0.5 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (100 g, 0.329 mol) was charged at room temperature. Glycine ethyl ester HCl (50.7 g, 0.362 mol) was charged at room temperature. N,N-Diisopropylethyl amine (64 g, 0.494 mol) was added carefully in to reaction mass at room temperature and heated the reaction mass at 65 to 70° C. Reaction mixture was stirred at 65 to 70° C. for 18 hours. The reaction mixture was quenched with addition of water (2.5 L).

Upon completion of water addition, the reaction mixture turns out to off white to yellow coloured slurry. Concentrated tetrahydrofuran below 55° C. in vacuo and reaction mixture was stirred at 25 to 35° C. for 1 hour. Solid material was filtered off and washed with water (3×0.20 L). Dried the compound in fan dryer at temperature 55 to 60° C. for 8 hours to get crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate as a solid.

Purification

In a 2 L fixed glass assembly, Methanol (1.15 L) was charged at room temperature. Crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (100 g) was charged at room temperature. The reaction mass was heated to 65 to 70° C. Reaction mass was stirred for 1 h at 65 to 70° C. Removed heating and cool the reaction mass to 25 to 35° C. Reaction mass stirred for 1 h at 25 to 35° C. Solid material was filtered off and washed with methanol (0.105 L). The product was dried under fan dryer at temperature 55 to 60° C. for 8 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 80% yield, as a solid. MS (ESI-MS): m/z 360.85 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.39 (m, 2H), 0.60-0.54 (m, 2H), 1.23-1.19 (t, 3H), 1.31-1.26 (m, 1H), 4.04-4.02 (d, 2H), 4.18-4.12 (q, 2H), 4.20-4.18 (d, 2H), 7.40-7.36 (m, 1H), 7.70-7.68 (d, 1H), 7.87-7.83 (m, 1H), 8.08-8.05 (dd, 1H), 10.27-10.24 (t, 1H). HPLC Purity: 99.84%

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, methanol (0.525 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (75 g, 0.208 mol) was charged at room temperature. Water (0.30 L) was charged at room temperature. Sodium hydroxide solution (20.8 g, 0.520 mol) in water (0.225 L) was added carefully at 30 to 40° C. Upon completion of addition of sodium hydroxide solution, the reaction mass turned to clear solution. Reaction mixture stirred for 30 minutes at 30 to 40° C. Diluted the reaction by addition of water (2.1 L). Precipitate the solid by addition of hydrochloric acid solution (75 mL) in water (75 mL). Upon completion of addition of hydrochloric acid solution, the reaction mass turned to off white colored thick slurry. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with water (4×0.375 L). The compound was dried under fan dryer at temperature 25 to 35° C. for 6 hours and then dried for 4 hours at 50 to 60° C. to get (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Polymorphic Data (XRPD):

References[edit]

^ “Zydus receives DCGI approval for new drug Oxemia; what you need to know”.
^ CDSCO, SEC Committee. “SEC meeting to examine IND proposals, dated 29.12.2021”. CDSCO website Govt of India. CDSCO. Retrieved 19 January 2022.
^ Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. (January 2018). “Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers”. Clinical Pharmacokinetics. 57 (1): 87–102. doi:10.1007/s40262-017-0551-3. PMC 5766731. PMID 28508936.
^ Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Patel NB, Nakrani VB, Shaikh FA, Patel HV; on behalf of the ZYAN1 Trial Investigators. Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study. Am J Nephrol. 2019 May 21;49(6):470-478. doi: 10.1159/000500232.
^ “Zydus Cadila announces phase III clinical trials of Desidustat”. 17 April 2019. Retrieved 20 April 2019 – via The Hindu BusinessLine.
^ Jain MR, Joharapurkar AA, Pandya V, Patel V, Joshi J, Kshirsagar S, et al. (February 2016). “Pharmacological Characterization of ZYAN1, a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia”. Drug Research. 66 (2): 107–12. doi:10.1055/s-0035-1554630. PMID 26367279.
^ Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR (August 2018). “Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases”. Journal of Medicinal Chemistry. 61 (16): 6964–6982. doi:10.1021/acs.jmedchem.7b01686. PMID 29712435.
^ Jain M, Joharapurkar A, Patel V, Kshirsagar S, Sutariya B, Patel M, et al. (January 2019). “Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation”. European Journal of Pharmacology. 843: 113–120. doi:10.1016/j.ejphar.2018.11.023. PMID 30458168. S2CID 53943666.
^ Market, Capital (20 January 2020). “Zydus enters into licensing agreement with China Medical System Holdings”. Business Standard India. Retrieved 20 January 2020 – via Business Standard.
^ Joharapurkar, Amit; Patel, Vishal; Kshirsagar, Samadhan; Patel, Maulik; Savsani, Hardikkumar; Jain, Mukul (22 January 2021). “Prolyl hydroxylase inhibitor desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines and oxidative stress”. Drug Development Research. 82 (6): 852–860. doi:10.1002/ddr.21792. PMID 33480036. S2CID 231680317.
^ “Zydus’ trials of Desidustat shows positive results for Covid-19 management”. The Hindu Business Line. The Hindu. Retrieved 25 January 2021.
^ “Zydus receives approval from USFDA to initiate clinical trials of Desidustat in cancer patients receiving chemotherapy”. PipelineReview.com. La Merie Publishing. Retrieved 22 January 2021.
^ “Stock Share Price | Get Quote | BSE”.

ANALYSIS

https://patentscope.wipo.int/search/en/result.jsf?inchikey=IKRKQQLJYBAPQT-UHFFFAOYSA-N

Countries

Desidustat
Clinical data

Other names	ZYAN1
Identifiers
IUPAC name [show]
CAS Number	1616690-16-4
UNII	Y962PQA4KS
Chemical and physical data
Formula	C₁₆H₁₆N₂O₆
Molar mass	332.312 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C1CC1CON2C3=CC=CC=C3C(=C(C2=O)C(=O)NCC(=O)O)O
InChI [hide] InChI=1S/C16H16N2O6/c19-12(20)7-17-15(22)13-14(21)10-3-1-2-4-11(10)18(16(13)23)24-8-9-5-6-9/h1-4,9,21H,5-8H2,(H,17,22)(H,19,20) Key:IKRKQQLJYBAPQT-UHFFFAOYSA-N

Date

CTID	Title	Phase	Status	Date
NCT04215120	Desidustat in the Treatment of Anemia in CKD on Dialysis Patients	Phase 3	Recruiting	2020-01-02
NCT04012957	Desidustat in the Treatment of Anemia in CKD	Phase 3	Recruiting	2019-12-24

////////// DESIDUSTAT, ZYDUS CADILA, COVID 19, CORONA VIRUS, PHASE 3, ZYAN 1, OXEMIA, APPROVALS 2022, INDIA 2022

breakingnewspharma hashtag on Twitter

GST-HG-121

June 4, 2020 12:52 pm / Leave a comment

GST-HG-121

mw 431.4

C23 H29 N07

Fujian Cosunter Pharmaceutical Co Ltd

Preclinical for the treatment of hepatitis B virus infection

This compound was originally claimed in WO2018214875 , and may provide the structure of GST-HG-121 , an HBsAg inhibitor which is being investigated by Fujian Cosunter for the treatment of hepatitis B virus infection; in June 2019, an IND application was planned in the US and clinical trials of the combination therapies were expected in 2020. Fujian Cosunter is also investigating GST-HG-131 , another HBsAg secretion inhibitor, although this appears to be being developed only as a part of drug combination.

WO2017013046A1

PATENT

WO2018214875

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214875&_cid=P21-KB0QYA-12917-1

Example 6

Step A: Maintaining at 0 degrees Celsius, lithium aluminum hydride (80.00 g, 2.11 mol, 2.77 equiv) was added to a solution of 6-1 (100.00 g, 762.36 mmol, 1.00 equiv) in tetrahydrofuran (400.00 mL). The solution was stirred at 10 degrees Celsius for 10 hours. Then, 80.00 ml of water was added to the reaction solution with stirring, and 240.00 ml of 15% aqueous sodium hydroxide solution was added, and then 80.00 ml of water was added. The resulting suspension was stirred at 10 degrees Celsius for 20 minutes, and filtered to obtain a colorless clear liquid. Concentrate under reduced pressure to obtain compound 6-2.

¹ H NMR (400 MHz, deuterated chloroform) δ = 3.72 (dd, J = 3.9, 10.2 Hz, 1H), 3.21 (t, J = 10.2 Hz, 1H), 2.51 (dd, J = 3.9, 10.2 Hz, 1H ), 0.91(s, 9H)

Step B: Dissolve 6-2 (50.00 g, 426.66 mmol) and triethylamine (59.39 mL, 426.66 mmol) in dichloromethane (500.00 mL), di-tert-butyl dicarbonate (92.19 g, 422.40 mmol) Mol) was dissolved in dichloromethane (100.00 ml) and added dropwise to the previous reaction solution at 0 degrees Celsius. The reaction solution was then stirred at 25 degrees Celsius for 12 hours. The reaction solution was washed with saturated brine (600.00 mL), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and spin-dried, and then recrystallized with methyl tert-butyl ether/petroleum ether (50.00/100.00) to obtain compound 6-3 .

¹ H NMR (400 MHz, deuterated chloroform) δ 4.64 (br s, 1H), 3.80-3.92 (m, 1H), 3.51 (br d, J = 7.09 Hz, 2H), 2.17 (br s, 1H), 1.48 (s, 9H), 0.96 (s, 9H).

Step C: Dissolve thionyl chloride (100.98 ml, 1.39 mmol) in acetonitrile (707.50 ml), 6-3 (121.00 g, 556.82 mmol) in acetonitrile (282.90 ml), and drop at minus 40 degrees Celsius After adding to the last reaction solution, pyridine (224.72 mL, 2.78 mol) was added to the reaction solution in one portion. The ice bath was removed, and the reaction solution was stirred at 5-10 degrees Celsius for 1 hour. After spin-drying the solvent under reduced pressure, ethyl acetate (800.00 ml) was added, and a solid precipitated, which was filtered, and the filtrate was concentrated under reduced pressure. Step 2: The obtained oil and water and ruthenium trichloride (12.55 g, 55.68 mmol) were dissolved in acetonitrile (153.80 ml), and sodium periodate (142.92 g, 668.19 mmol) was suspended in water (153.80 ml ), slowly add to the above reaction solution, and the final reaction mixture is stirred at 5-10 degrees Celsius for 0.15 hours. The reaction mixture was filtered to obtain a filtrate, which was extracted with ethyl acetate (800.00 mL×2). The organic phase was washed with saturated brine (800.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Column purification (silica, petroleum ether/ethyl acetate = 50/1 to 20/1) gave compound 6-4.

¹ H NMR (400 MHz, deuterated chloroform) δ 4.49-4.55 (m, 1H), 4.40-4.44 (m, 1H), 4.10 (d, J = 6.15 Hz, 1H), 1.49 (s, 9H), 0.94 (s,9H).

[0230]

Step D: Dissolve 6-5 (100.00 g, 657.26 mmol) in acetonitrile (1300.00 mL), add potassium carbonate (227.10 g, 1.64 mol) and 1-bromo-3-methoxypropane (110.63 g, 722.99 Millimoles). The reaction solution was stirred at 85 degrees Celsius for 6 hours. The reaction solution was extracted with ethyl acetate 600.00 ml (200.00 ml×3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain compound 6-6.

[0231]

¹ H NMR (400 MHz, deuterated chloroform) δ 9.76-9.94 (m, 1H), 7.42-7.48 (m, 2H), 6.98 (d, J=8.03 Hz, 1H), 4.18 (t, J=6.53 Hz , 2H), 3.95 (s, 3H), 3.57 (t, J = 6.09 Hz, 2H), 3.33-3.39 (m, 3H), 2.13 (quin, J = 6.34 Hz, 2H).

[0232]

Step E: Dissolve 6-6 (70.00 g, 312.15 mmol) in methylene chloride, add m-chloroperoxybenzoic acid (94.27 g, 437.01 mmol), and the reaction was stirred at 50 degrees Celsius for 2 hours. After cooling the reaction solution, it was filtered, the filtrate was extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution 2000.00 ml (400.00 ml × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A brown oil was obtained. After dissolving with as little methanol as possible, a solution of 2 mol per liter of potassium hydroxide (350.00 ml) was slowly added (exothermic). The dark colored reaction solution was stirred at room temperature for 20 minutes, and the reaction solution was adjusted to pH 5 with 37% hydrochloric acid. It was extracted with ethyl acetate 400.00 ml (200.00 ml×2), and the organic phase was washed with saturated brine 200.00 ml (100.00 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 6-7.

¹ H NMR (400 MHz, deuterated chloroform) δ 6.75 (d, J = 8.53 Hz, 1H), 6.49 (d, J = 2.89 Hz, 1H), 6.36 (dd, J = 2.82, 8.60 Hz, 1H), 4.07 (t, J = 6.40 Hz, 2H), 3.82 (s, 3H), 3.60 (t, J = 6.15 Hz, 2H), 3.38 (s, 3H), 2.06-2.14 (m, 2H).

Step F: Dissolve 6-7 (33.00 g, 155.48 mmol) in tetrahydrofuran (330.00 mL), add paraformaldehyde (42.02 g, 466.45 mmol), magnesium chloride (29.61 g, 310.97 mmol), triethylamine (47.20 g, 466.45 mmol, 64.92 mL). The reaction solution was stirred at 80 degrees Celsius for 8 hours. After the reaction was completed, it was quenched with 2 molar hydrochloric acid solution (200.00 ml) at 25°C, then extracted with ethyl acetate 600.00 ml (200.00 ml×3), and the organic phase was washed with saturated brine 400.00 ml (200.00 ml×2). Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The residue was washed with ethanol (30.00 ml) and filtered to obtain a filter cake. Thus, compound 6-8 is obtained.

¹ H NMR (400 MHz, deuterated chloroform) δ 11.29 (s, 1H), 9.55-9.67 (m, 1H), 6.83 (s, 1H), 6.42 (s, 1H), 4.10 (t, J=6.48 Hz , 2H), 3.79 (s, 3H), 3.49 (t, J = 6.05 Hz, 2H), 3.28 (s, 3H), 2.06 (quin, J = 6.27 Hz, 2H)

Step G: Dissolve 6-8 (8.70 g, 36.21 mmol) in N,N-dimethylformamide (80.00 mL), add potassium carbonate (10.01 g, 72.42 mmol) and 6-4 (11.13 g) , 39.83 mmol), the reaction solution was stirred at 50 degrees Celsius for 2 hours. The reaction solution was quenched with 1.00 mol/L aqueous hydrochloric acid solution (200.00 mL), and extracted with ethyl acetate (150.00 mL×2). The combined organic phase was washed with water (150.00 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6-9.

¹ H NMR (400 MHz, deuterated chloroform) δ 10.31 (s, 1H), 7.34 (s, 1H), 6.57 (s, 1H), 4.18-4.26 (m, 3H), 4.07 (dd, J=5.33, 9.60Hz, 1H), 3.88(s, 4H), 3.60(t, J=5.96Hz, 2H), 3.39(s, 3H), 2.17(quin, J=6.21Hz, 2H), 1.47(s, 9H) , 1.06 (s, 9H).

Step H: Dissolve 6-9 (15.80 g, 35.95 mmol) in dichloromethane (150.00 mL) and add trifluoroacetic acid (43.91 mL, 593.12 mmol). The reaction solution was stirred at 10 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure and spin-dried, sodium bicarbonate aqueous solution (100.00 mL) was added, and dichloromethane (100.00 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6-10.

¹ H NMR (400 MHz, deuterated chloroform) δ 8.40 (s, 1H), 6.80 (s, 1H), 6.51 (s, 1H), 4.30 (br d, J = 12.35 Hz, 1H), 4.04-4.11 ( m, 3H), 3.79 (s, 3H), 3.49 (t, J = 5.99 Hz, 2H), 3.36 (br d, J = 2.93 Hz, 1H), 3.28 (s, 3H), 2.06 (quin, J = 6.24Hz, 2H), 1.02(s, 9H).

Step I: Dissolve 6-10 (5.00 g, 15.56 mmol) in toluene (20.00 mL) and add 6-11 (8.04 g, 31.11 mmol). The reaction solution was stirred at 120 degrees Celsius for 12 hours under nitrogen protection. The reaction solution was quenched with water (100.00 mL), extracted with ethyl acetate (100.00 mL×2), the combined organic phases were washed with water (80.00 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column. Then purified by high-performance liquid chromatography (column: Phenomenex luna C18 250*50 mm*10 microns; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 35%-70%, 25 minutes) Compound 6-12 is obtained.

¹ H NMR (400 MHz, deuterated chloroform) δ 7.95 (s, 1H), 6.59 (s, 1H), 6.40 (s, 1H), 5.15-5.23 (m, 1H), 4.35-4.41 (m, 2H) , 4.08-4.19 (m, 2H), 3.94-4.00 (m, 2H), 3.72 (s, 3H), 3.61-3.67 (m, 1H), 3.46 (dt, J=1.96, 5.99Hz, 2H), 3.27 (s, 3H), 3.01-3.08 (m, 1H), 2.85-2.94 (m, 1H), 1.97-2.01 (m, 2H), 1.18-1.22 (m, 3H), 1.04 (s, 9H).

Step J: Dissolve 6-12 (875.00 mg, 1.90 mmol) in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), and add tetrachlorobenzoquinone (1.40 g, 5.69 mmol). The reaction solution was stirred at 120 degrees Celsius for 12 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium carbonate solution (50.00 ml) and ethyl acetate (60.00 ml) were added. The mixed solution was stirred at 10-15 degrees Celsius for 20 minutes, and the liquid was separated to obtain an organic phase. Add 2.00 mol/L aqueous hydrochloric acid solution (60.00 mL) to the organic phase, stir at 10-15 degrees Celsius for 20 minutes, and separate the liquid. Wash the organic phase with 2 mol/L aqueous hydrochloric acid solution (60.00 mL×2), separate the liquid, and separate the water phase A 2 mol/L aqueous sodium hydroxide solution (200.00 ml) and dichloromethane (200.00 ml) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 6-13.

[0243]

¹ H NMR (400 MHz, deuterated chloroform) δ 7.98-8.78 (m, 1H), 6.86 (s, 1H), 6.43-6.73 (m, 2H), 4.41-4.48 (m, 1H), 4.28-4.38 ( m, 2H), 4.03-4.11 (m, 2H), 3.93 (br s, 1H), 3.80 (s, 3H), 3.47-3.52 (m, 3H), 3.29 (s, 3H), 2.06 (quin, J = 6.24 Hz, 2H), 1.33 (t, J = 7.15 Hz, 2H), 0.70-1.25 (m, 10H).

[0244]

Step K: Dissolve 6-13 (600.00 mg, 1.31 mmol) in methanol (6.00 mL), and add 4.00 mol/L aqueous sodium hydroxide solution (2.00 mL, 6.39 equiv). The reaction solution was stirred at 15 degrees Celsius for 0.25 hours. The reaction solution was adjusted to pH=3-4 with a 1.00 mol/L hydrochloric acid aqueous solution, and then extracted with dichloromethane (50.00 mL×3). The organic phases were combined, washed with saturated brine (50.00 mL), and dried over anhydrous sodium sulfate. , Filtered and concentrated under reduced pressure to obtain Example 6.

[0245]

ee value (enantiomeric excess): 100%.

[0246]

SFC (Supercritical Fluid Chromatography) method: Column: Chiralcel OD-3 100 mm x 4.6 mm ID, 3 μm mobile phase: methanol (0.05% diethylamine) in carbon dioxide from 5% to 40% Flow rate: 3 ml per minute Wavelength: 220 nm.

[0247]

¹ H NMR (400 MHz, deuterated chloroform) δ 15.72 (br s, 1H), 8.32-8.93 (m, 1H), 6.60-6.93 (m, 2H), 6.51 (br s, 1H), 4.38-4.63 ( m, 2H), 4.11 (br dd, J = 4.52, 12.23 Hz, 3H), 3.79-3.87 (m, 3H), 3.46-3.54 (m, 2H), 3.29 (s, 3H), 2.07 (quin, J = 6.24 Hz, 2H), 0.77-1.21 (m, 9H).

PATENT

WO-2020103924

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020103924&tab=FULLTEXT&_cid=P21-KB0QP8-09832-1

Novel crystalline forms of 11-oxo-7,11-dihydro-6H-benzo[f]pyrido[1,2-d][1,4]azepine, a hepatitis B surface antigen and HBV replication inhibitor, useful for treating HBV infection.

Hepatitis B virus, or hepatitis B for short, is a disease caused by Hepatitis B Virus (HBV) infection of the body. Hepatitis B virus is a hepatotropic virus, which mainly exists in liver cells and damages liver cells, causing inflammation, necrosis, and fibrosis of liver cells. There are two types of viral hepatitis, acute and chronic. Acute hepatitis B in most adults can heal itself through its own immune mechanism. But chronic hepatitis B (CHB) has become a great challenge for global health care, and it is also the main cause of chronic liver disease, cirrhosis and liver cancer (HCC). It is estimated that 2 billion people worldwide are infected with chronic hepatitis B virus, and more than 350 million people have developed into hepatitis B. Nearly 600,000 people die each year from complications of chronic hepatitis B. my country is a high incidence area of hepatitis B. There are many patients with accumulated hepatitis B, and the harm is serious. According to data, there are about 93 million people with hepatitis B virus infection in China, and about 20 million of them are diagnosed with chronic hepatitis B, of which 10%-20% can evolve into cirrhosis and 1%-5% can develop into Liver cancer.

The key to the functional cure of hepatitis B is to remove HBsAg (hepatitis B virus surface antigen) and produce surface antibodies. HBsAg quantification is a very important biological indicator. In patients with chronic infection, few HBsAg reductions and seroconversion can be observed, which is the end point of current treatment.

The surface antigen protein of hepatitis B virus (HBV) plays a very important role in the process of HBV invading liver cells, and is of great significance for the prevention and treatment of HBV infection. Surface antigen proteins include large (L), medium (M) and small (S) surface antigen proteins, sharing a common C-terminal S region. They are expressed from an open reading frame, and their different lengths are determined by the three AUG start codons in the reading frame. These three surface antigen proteins include pre-S1/pre-S2/S, pre-S2/S and S domains. The HBV surface antigen protein is integrated into the endoplasmic reticulum (ER) membrane and is initiated by the N-terminal signal sequence. They not only constitute the basic structure of the virion, but also form spherical and filamentous subviral particles (SVPs, HBsAg), aggregated in the ER, host ER and pre-Golgi apparatus, SVP contains most S surface antigen proteins. The L protein is crucial in the interaction between viral morphogenesis and nucleocapsid, but it is not necessary for the formation of SVP. Due to their lack of nucleocapsid, the SVPs are non-infectious. SVPs are greatly involved in disease progression, especially the immune response to hepatitis B virus. In the blood of infected persons, the amount of SVPs is at least 10,000 times the number of viruses, trapping the immune system and weakening the body’s immune response to hepatitis B virus. HBsAg can also inhibit human innate immunity, can inhibit the production of cytokines induced by polysaccharide (LPS) and IL-2, inhibit the DC function of dendritic cells, and LPS interfere with ERK-1/2 and c-Jun N-terminal interfering kinase-1 2 Inducing activity in monocytes. It is worth noting that the disease progression of cirrhosis and hepatocellular carcinoma is also largely related to the persistent secretion of HBsAg. These findings indicate that HBsAg plays an important role in the development of chronic hepatitis.

The currently approved anti-HBV drugs are mainly immunomodulators (interferon-α and pegylated interferon-α-2α) and antiviral drugs (lamivudine, adefovir dipivoxil, entecavir, and Bifudine, Tenofovir, Kravudine, etc.). Among them, antiviral drugs belong to the class of nucleotide drugs, and their mechanism of action is to inhibit the synthesis of HBV DNA, and cannot directly reduce the level of HBsAg. As with prolonged treatment, nucleotide drugs show HBsAg clearance rate similar to natural observations.

Existing therapies in the clinic are not effective in reducing HBsAg. Therefore, the development of small molecule oral inhibitors that can effectively reduce HBsAg is urgently needed in clinical medicine.

Roche has developed a surface antigen inhibitor called RG7834 for the treatment of hepatitis B, and reported the drug efficacy of the compound in the model of woodchuck anti-hepatitis B: when using RG7834 as a single drug, it can reduce the surface of 2.57 Logs Antigen, reduced HBV-DNA by 1.7 Logs. The compound has good activity, but in the process of molecular synthesis, the isomers need to be resolved, which reduces the yield and increases the cost.

WO2017013046A1 discloses a series of 2-oxo-7,8-dihydro-6H-pyrido[2,1,a][2]benzodiazepine-3-for the treatment or prevention of hepatitis B virus infection Carboxylic acid derivatives. The IC ₅₀ of Example 3, the highest activity of this series of fused ring compounds , is 419 nM, and there is much room for improvement in activity. The chiral centers contained in this series of compounds are difficult to synthesize asymmetrically. Generally, the 7-membered carbocyclic ring has poor water solubility and is prone to oxidative metabolism.

Example 1 Preparation of compound of formula (I)

[0060]

Step A: Maintaining at 0 degrees Celsius, to a solution of compound 1 (100.00 g, 762.36 mmol, 1.00 equiv) in tetrahydrofuran (400.00 mL) was added lithium aluminum hydride (80.00 g, 2.11 mol, 2.77 equiv). The solution was stirred at 10 degrees Celsius for 10 hours. Then, 80.00 ml of water was added to the reaction solution with stirring, and 240.00 ml of 15% aqueous sodium hydroxide solution was added, and then 80.00 ml of water was added. The resulting suspension was stirred at 10 degrees Celsius for 20 minutes, and filtered to obtain a colorless clear liquid. Concentrate under reduced pressure to obtain compound 2.

Step B: Dissolve compound 2 (50.00 g, 426.66 mmol) and triethylamine (59.39 mL, 426.66 mmol) in dichloromethane (500.00 mL), di-tert-butyl dicarbonate (92.19 g, 422.40 mmol) ) Was dissolved in dichloromethane (100.00 ml) and added dropwise to the previous reaction solution at 0 degrees Celsius. The reaction solution was then stirred at 25 degrees Celsius for 12 hours. The reaction solution was washed with saturated brine (600.00 ml), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and spin-dried, and then recrystallized from methyl tert-butyl ether/petroleum ether (50.00/100.00) to obtain compound 3.

Step C: Dissolve thionyl chloride (100.98 ml, 1.39 mmol) in acetonitrile (707.50 ml), compound 3 (121.00 g, 556.82 mmol) in acetonitrile (282.90 ml), and add dropwise at minus 40 degrees Celsius To the last reaction solution, after the dropwise addition, pyridine (224.72 mL, 2.78 mol) was added to the reaction solution in one portion. The ice bath was removed, and the reaction solution was stirred at 5-10 degrees Celsius for 1 hour. After spin-drying the solvent under reduced pressure, ethyl acetate (800.00 ml) was added, and a solid precipitated, which was filtered, and the filtrate was concentrated under reduced pressure. Step 2: The obtained oil and water and ruthenium trichloride (12.55 g, 55.68 mmol) were dissolved in acetonitrile (153.80 ml), and sodium periodate (142.92 g, 668.19 mmol) was suspended in water (153.80 ml ), slowly add to the above reaction solution, and the final reaction mixture is stirred at 5-10 degrees Celsius for 0.15 hours. The reaction mixture was filtered to obtain a filtrate, which was extracted with ethyl acetate (800.00 mL×2). The organic phase was washed with saturated brine (800.00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. Column purification (silica, petroleum ether/ethyl acetate = 50/1 to 20/1) gave compound 4.

Step D: Dissolve compound 5 (100.00 g, 657.26 mmol) in acetonitrile (1300.00 mL), add potassium carbonate (227.10 g, 1.64 mol) and 1-bromo-3-methoxypropane (110.63 g, 722.99 mmol) Mole). The reaction solution was stirred at 85 degrees Celsius for 6 hours. The reaction solution was extracted with ethyl acetate 600.00 ml (200.00 ml×3), dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure to obtain compound 6.

Step E: Compound 6 (70.00 g, 312.15 mmol) was dissolved in methylene chloride, m-chloroperoxybenzoic acid (94.27 g, 437.01 mmol) was added, and the reaction was stirred at 50 degrees Celsius for 2 hours. After cooling the reaction solution, it was filtered, the filtrate was extracted with dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution 2000.00 ml (400.00 ml × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A brown oil was obtained. After dissolving with as little methanol as possible, a solution of 2 mol per liter of potassium hydroxide (350.00 ml) was slowly added (exothermic). The dark colored reaction solution was stirred at room temperature for 20 minutes, and the reaction solution was adjusted to pH 5 with 37% hydrochloric acid. It was extracted with ethyl acetate 400.00 ml (200.00 ml×2), the organic phase was washed with saturated brine 200.00 ml (100.00 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7.

[0066]

Step F: Compound 7 (33.00 g, 155.48 mmol) was dissolved in tetrahydrofuran (330.00 mL), paraformaldehyde (42.02 g, 466.45 mmol), magnesium chloride (29.61 g, 310.97 mmol), triethylamine ( 47.20 g, 466.45 mmol, 64.92 mL). The reaction solution was stirred at 80 degrees Celsius for 8 hours. After the reaction was completed, it was quenched with 2 molar hydrochloric acid solution (200.00 ml) at 25°C, then extracted with ethyl acetate 600.00 ml (200.00 ml×3), and the organic phase was washed with saturated brine 400.00 ml (200.00 ml×2). Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. The residue was washed with ethanol (30.00 ml) and filtered to obtain a filter cake. Thus, compound 8 is obtained.

Step G: Dissolve compound 8 (8.70 g, 36.21 mmol) in N,N-dimethylformamide (80.00 mL), add potassium carbonate (10.01 g, 72.42 mmol) and compound 4 (11.13 g, 39.83 Mmol), the reaction solution was stirred at 50 degrees Celsius for 2 hours. The reaction solution was quenched with 1.00 mol/L aqueous hydrochloric acid solution (200.00 mL), and extracted with ethyl acetate (150.00 mL×2). The combined organic phase was washed with water (150.00 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 9.

Step H: Compound 9 (15.80 g, 35.95 mmol) was dissolved in dichloromethane (150.00 mL), and trifluoroacetic acid (43.91 mL, 593.12 mmol) was added. The reaction solution was stirred at 10 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure and spin-dried, sodium bicarbonate aqueous solution (100.00 mL) was added, and dichloromethane (100.00 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 10.

Step I: Compound 10 (5.00 g, 15.56 mmol) was dissolved in toluene (20.00 mL), and compound 11 (8.04 g, 31.11 mmol) was added. The reaction solution was stirred at 120°C for 12 hours under nitrogen protection. The reaction solution was quenched with water (100.00 mL), extracted with ethyl acetate (100.00 mL×2), the combined organic phases were washed with water (80.00 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column. Purified by high-performance liquid chromatography (column: Phenomenex luna C18 250×50 mm×10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 35%-70%, 25 minutes) Compound 12 is obtained.

Step J: Compound 12 (875.00 mg, 1.90 mmol) was dissolved in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), and tetrachlorobenzoquinone (1.40 g, 5.69 mmol) was added. The reaction solution was stirred at 120 degrees Celsius for 12 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium carbonate solution (50.00 ml) and ethyl acetate (60.00 ml) were added. The mixed solution was stirred at 10-15 degrees Celsius for 20 minutes, and the liquid was separated to obtain an organic phase. Add 2.00 mol/L aqueous hydrochloric acid solution (60.00 mL) to the organic phase, stir at 10-15 degrees Celsius for 20 minutes, and separate the liquid. Wash the organic phase with 2 mol/L aqueous hydrochloric acid solution (60.00 mL×2), separate the liquid, and separate the water phase A 2 mol/L aqueous sodium hydroxide solution (200.00 ml) and dichloromethane (200.00 ml) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 13.

Step K: Compound 13 (600.00 mg, 1.31 mmol) was dissolved in methanol (6.00 mL), and 4.00 mol/L aqueous sodium hydroxide solution (2.00 mL, 6.39 equiv) was added. The reaction solution was stirred at 15 degrees Celsius for 0.25 hours. The reaction solution was adjusted to pH=3-4 with a 1.00 mol/L hydrochloric acid aqueous solution, and then extracted with dichloromethane (50.00 mL×3). The organic phases were combined, washed with saturated brine (50.00 mL), and dried over anhydrous sodium sulfate , Filtered and concentrated under reduced pressure to obtain the compound of formula (I). ee value (enantiomeric excess): 100%.

SFC (supercritical fluid chromatography) method:

Column: Chiralcel OD-3 100 mm x 4.6 mm size, 3 microns.

Mobile phase: methanol (0.05% diethylamine) in carbon dioxide, from 5% to 40%.

Flow rate: 3 ml per minute.

Wavelength: 220 nm.

////////////GST-HG-121, Fujian Cosunter, Preclinical , hepatitis B, virus infection

O=C(O)C1=CN2C(=CC1=O)c3cc(OC)c(OCCCOC)cc3OC[C@H]2C(C)(C)C

NARONAPRIDE

May 26, 2020 9:09 am / 1 Comment on NARONAPRIDE

Naronapride | C27H41ClN4O5 - PubChem

Naronapride | ATI-7505 | CAS#860174-12-5 | 860169-57-9 | 5-HT(4 ...

NARONAPRIDE

860174-12-5

Average: 537.1

C₂₇H₄₁ClN₄O₅

ATI 7505 / ATI-7505

(3R)-1-azabicyclo[2.2.2]octan-3-yl 6-[(3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl]hexanoate

INGREDIENT	UNII	CAS
Naronapride dihydrochloride	898PE2W8US	860169-57-9

860174-12-5 (free base) 860169-57-9 (HCl)

Naronapride (free base), also known as ATI-7505, is a highly selective, high-affinity 5-HT(4) receptor agonist for gastrointestinal motility disorders. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

Investigated for use/treatment in gastroesophageal reflux disease (GERD) and gastroparesis.

Renexxion , presumed to have been spun-out from Armetheon , under license from ARYx Therapeutics is developing naronapride (ATI-7505; phase 2 clinical in February 2020), an analog of the gastroprokinetic 5-HT 4 agonist cisapride identified using ARYx’s RetroMetabolic platform technology (ARM), for the oral treatment of upper GI disorders. In September 2018, this was still the case . PATENT

WO2005068461

NEW PATENT

WO-2020096911

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020096911&tab=PCTDESCRIPTION&_cid=P21-KANOVN-53661-1

Process for preparing trihydrate salt of naronapride hydrochloride as 5-HT 4 receptor agonist useful for treating gastrointestinal disorders such as dyspepsia, gastroparesis, constipation, post-operative ileus. Appears to be the first filing from the assignee and the inventors on this compound,

In some aspects, provided herein is a method of making a trihydrate form of (3S, 4R, 3’R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-l-yl]-hexanoic acid l-azabicyclo[2.2.2]oct-3’-yl ester di-hydrochloride salt, which has the following formula:

Example 5: NMR Characterization of the Trihydrate

[0282] ^-Nuclear Magnetic Resonance Spectroscopy (‘H-NMR) : Approximately 6 mg of the trihydrate was dissolved in in 1 g of deuterated solvent (dimethylsulfoxide (DMSO)-C45 99.9% d, with 0.05% v/v tetramethyl silane (TMS)). A Varian Gemini 300 MHz FT-NMR spectrometer was used to obtain the ¾-NMK spectrum. A list of the peaks is provided in Table 1 below. A representative ‘H-NMR spectrum is provided in FIG. 6.

Table 1. ‘H-NMR peak list for trihydrate

[0283] ¹³ C-Nuclear Magnetic Resonance Spectroscopy ( ¹³C-NMR ): Approximately 46 mg of the trihydrate was dissolved in 1 mL of deuterated solvent (deuterium oxide, Aldrich, 99.9% D, TPAS 0.75%). The ¹³C-NMR spectrum was obtained using a Varian Gemini 300 MHz FT-NMR spectrometer. A list of the peaks is provided in Table 2 below. A representative ¹³C-NMR spectrum is provided in FIG. 7.

Table 2. ¹³C-NMR peak list for trihydrate

PATENT

US10570127 claiming composition (eg tablet) comprising a trihydrate form of naronapride.

patent

ARYX THERAPEUTICS, WO2005/68461, A1, (2005)

Methods

titanium tetraethoxide; toluene;

Reactants can be synthesized in 1 step.
ARYX THERAPEUTICS, WO2005/68461, A1, (2005) The ester (1 part by weight) and (R)-3-Quinuclidinol (about 1.12 part by weight) were suspended in toluene before slowly adding titanium (IV) ethoxide (about 0.5 part by weight) to the stirred suspens ion. The mixture was heated to about 91 °C under a stream of nitrogen, and partial vacuum was applie d to the flask through a distillation apparatus in order to azeotropically remove the ethanol. Addit ional toluene was added as needed to maintain a minimum solvent volume in the flask. The reaction was considered complete after about 33 hours. The mixture was cooled to about room temperature and ext racted five times with water. The organic layer was concentrated under reduced pressure and the resulting residue was redissolved in EtOH/iPrOH (about 1: 1 v/v) and then filtered through a 0.45 micron membrane filter to remove any particulates. Concentrated hydrochloric acid was added slowly to the stirred filtrate to precipitate out the desired product as the dihydrochloride salt. The resulting s uspension was stirred for several hours at room temperature and collected under vacuum filtration and rinsed with EtOH/tPrOH (1: 1; v/v) to provide 0.53 part by weight of the crude product salt. Crude dihydrochloride salt was resuspended in ethanol and heated to reflux before cooling to room temperature over about 1 hour. The product was collected under vacuum filtration and rinsed with ethanol an d then air-dried. The solids were resuspended in ethanol and warmed to about 55 °C to give a clear s olution before adding warm isopropanol and the product was allowed to precipitate by slow cooling to room temperature. The resulting suspension was stirred for several hours before vacuum filtering and rinsing with, e. g., isopropanol. The product was vacuum dried, initially at room temperature for several hours and then at about 55 °C until a constant weight was achieved.

Patent

Methods

dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; DMFA;

Reactants can be synthesized in 2 steps.
ARYX THERAPEUTICS, WO2007/28073, A2, (2007) Production of Compound IV and Compound VI[0394] A mixture of (+)-Comrhoound II (1 eq.), (R)-(-)-3-quinuclidinol HCl salt (1 eq.), EDAC (1 eq.) and DMAP (1 eq.) in DMF is heated at around 5OC overnight . After cooling and diluting with water, the mixture is purified by chromatography or by crystallization to provide Compound IV. Similarly, using (S)-(+)-quinuclidinol, Compound VI is obtained

REFERENCES

1: Jiang C, Xu Q, Wen X, Sun H. Current developments in pharmacological therapeutics for chronic constipation. Acta Pharm Sin B. 2015 Jul;5(4):300-9. doi: 10.1016/j.apsb.2015.05.006. Epub 2015 Jun 6. Review. PubMed PMID: 26579459; PubMed Central PMCID: PMC4629408.

2: Buchwald P, Bodor N. Recent advances in the design and development of soft drugs. Pharmazie. 2014 Jun;69(6):403-13. Review. PubMed PMID: 24974571.

3: Mozaffari S, Didari T, Nikfar S, Abdollahi M. Phase II drugs under clinical investigation for the treatment of chronic constipation. Expert Opin Investig Drugs. 2014 Nov;23(11):1485-97. doi: 10.1517/13543784.2014.932770. Epub 2014 Jun 24. Review. PubMed PMID: 24960333.

4: Shin A, Camilleri M, Kolar G, Erwin P, West CP, Murad MH. Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014 Feb;39(3):239-53. doi: 10.1111/apt.12571. Epub 2013 Dec 5. Review. PubMed PMID: 24308797.

5: Stevens JE, Jones KL, Rayner CK, Horowitz M. Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives. Expert Opin Pharmacother. 2013 Jun;14(9):1171-86. doi: 10.1517/14656566.2013.795948. Epub 2013 May 11. Review. PubMed PMID: 23663133.

6: Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy BE, Müller-Lissner S, Quigley EM, Schuurkes J, De Maeyer JH, Stanghellini V. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012 Apr;35(7):745-67. doi: 10.1111/j.1365-2036.2012.05011.x. Epub 2012 Feb 22. Review. PubMed PMID: 22356640; PubMed Central PMCID: PMC3491670.

7: Hoffman JM, Tyler K, MacEachern SJ, Balemba OB, Johnson AC, Brooks EM, Zhao H, Swain GM, Moses PL, Galligan JJ, Sharkey KA, Greenwood-Van Meerveld B, Mawe GM. Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology. 2012 Apr;142(4):844-854.e4. doi: 10.1053/j.gastro.2011.12.041. Epub 2012 Jan 4. PubMed PMID: 22226658; PubMed Central PMCID: PMC3477545.

8: Bowersox SS, Lightning LK, Rao S, Palme M, Ellis D, Coleman R, Davies AM, Kumaraswamy P, Druzgala P. Metabolism and pharmacokinetics of naronapride (ATI-7505), a serotonin 5-HT(4) receptor agonist for gastrointestinal motility disorders. Drug Metab Dispos. 2011 Jul;39(7):1170-80. doi: 10.1124/dmd.110.037564. Epub 2011 Mar 29. PubMed PMID: 21447732.

9: Tack J. Current and future therapies for chronic constipation. Best Pract Res Clin Gastroenterol. 2011 Feb;25(1):151-8. doi: 10.1016/j.bpg.2011.01.005. Review. PubMed PMID: 21382586.

10: Manabe N, Wong BS, Camilleri M. New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders. Expert Opin Investig Drugs. 2010 Jun;19(6):765-75. doi: 10.1517/13543784.2010.482927. Review. PubMed PMID: 20408739.

11: Sanger GJ. Translating 5-HT receptor pharmacology. Neurogastroenterol Motil. 2009 Dec;21(12):1235-8. doi: 10.1111/j.1365-2982.2009.01425.x. Review. PubMed PMID: 19906028.

12: Vakil N. New pharmacological agents for the treatment of gastroesophageal reflux disease. Rev Gastroenterol Disord. 2008 Spring;8(2):117-22. Review. PubMed PMID: 18641594.

13: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. PubMed PMID: 17805439.

14: Camilleri M, Vazquez-Roque MI, Burton D, Ford T, McKinzie S, Zinsmeister AR, Druzgala P. Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans. Neurogastroenterol Motil. 2007 Jan;19(1):30-8. PubMed PMID: 17187586.

////////////NARONAPRIDE, ATI 7505, ATI 7505,PHASE 2

CO[C@H]1CN(CCCCCC(=O)O[C@H]2CN3CCC2CC3)CC[C@H]1NC(=O)C1=C(OC)C=C(N)C(Cl)=C1

VOCLOSPORIN

April 30, 2020 6:14 am / 1 Comment on VOCLOSPORIN

ChemSpider 2D Image | Voclosporin | C63H111N11O12

Voclosporin | C63H111N11O12 - PubChem

Structure of VOCLOSPORIN

Voclosporin

Molecular FormulaC₆₃H₁₁₁N₁₁O₁₂
Average mass1214.622 Da

VOCLOSPORIN

(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-Ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4,6-heptadien-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,2 5,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

1,4,7,10,13,16,19,22,25,28,31-Undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone, 30-ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4,6-heptadien-1-yl]-1,4,7,10,12,15,19,25,28-nonamethyl-3,2 1-bis(1-methylethyl)-6,9,18,24-tetrakis(2-methylpropyl)-, (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-

2PN063X6B1

515814-01-4 [RN]

8889

SA247, ISAtx 247, ISAtx-247, ISAtx247, Luveniq, LX211,

The Greedy Vulture Accumulate under $3.50

Aurinia Pharmaceuticals (following its merger with Isotechnika ), in collaboration with licensee Paladin Labs (a subsidiary of Endo International plc ), 3SBio ,and ILJIN , is developing a capsule formulation of the immunosuppressant calcineurin inhibitor peptide voclosporin for the treatment of psoriasis, the prevention of organ rejection after transplantation, autoimmune disease including systemic lupus erythematosus and lupus nephritis, and nephrotic syndrome including focal segmental glomerulosclerosis;

Voclosporin is an experimental immunosuppressant drug being developed by Aurinia Pharmaceuticals. It is being studied as a potential treatment for lupus nephritis (LN) and uveitis.^[1] It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability.^[2] Voclosporin was discovered by Robert T. Foster and his team at Isotechnika in the mid 1990s.^[3] Isotechnika was founded in 1993 and merged with Aurinia Pharmaceuticals in 2013.

Initially, voclosporin was a mixture of equal proporations of cis and trans geometric isomers of amino acid-1 modified cyclosporin. Later, in collaboration with Roche in Basel, Switzerland, voclosporin’s manufacturing was changed to yield the predominantly trans isomer which possesses most of the beneficial effect of the drug (immunosuppression) in the treatment of organ transplantation and autoimmune diseases.

Patent

WO-2020082061

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020082061&_cid=P12-K9MDK8-59382-1

Novel crystalline forms of voclosporin which is a structural analog of cyclosporine A as calcineurin signal-transduction pathway inhibitor useful for treating lupus nephritis.

Voclosporin is a structural analog of cyclosporine A, with an additional single carbon extension that has a double-bond on one side chain. Voclosporin has the chemical name (3S,6S,9S,l2R,l5S,l8S,2lS,24S,30S,33S)-30-Ethyl-33-[(lR,2R,4E)-l-hydroxy-2-methyl-4,6-heptadien-l-yl]-6,9,l8,24-tetraisobutyl-3,2l-diisopropyl-l,4,7,l0,l2,l5,l9,25,28-nonamethyl-l,4,7,l0,l3,l6,l9,22,25,28,3 l-undecaazacyclotritriacontane-2,5,8,l l,l4,l7,20,23,26,29,32-undecone and the following chemical structure:

Voclosporin is reported to be a semisynthetic structural analogue of cyclosporine that exerts its immunosuppressant effects by inhibition of the calcineurin signal-transduction pathway and is in Phase 3 Clinical Development for Lupus Nephritis.

[0003] Voclosporin and process for preparation thereof are known from International Patent Application No. WO 1999/18120.

[0004] Certain mixtures of cis and trans-isomers of cyclosporin A analogs referred to as

ISA_TX247 in different ratios are known from U.S. Patent No. 6,998,385, U.S. Patent No. 7,332,472 and U.S. Patent No. 9,765,119.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Voclosporin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (¹³C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active

pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

[0008] For at least these reasons, there is a need for solid state forms (including solvated forms) of Voclosporin and salts thereof.

HPLC method:

Method description

Column: Zorbax SB C18, 1.8 pm, 100×2.1 mm

Mobile phase: A: 38 ACN : 7 TBME : 55 voda : 0.02 H₃P0₄ (V/V/V/V)

B: 70 ACN : 7 TBME : 23 voda : 0.02 H P0₄ (V/V/V/V)

Flow rate: 0.5 mL/min

Gradient

Analysis time: 26 minutes + 3 minutes equilibration

Injection volume: 3.0 pL

Column temperature: 90 °C

Diluent: Ethanol

Detection: UV, 210 nm

EXAMPLES

[0095] The starting material Voclosporin crude may be obtained according to ET.S. Patent No. 6,998,385 ETnless otherwise indicated, the purity is determined by HPLC (area percent). The crude product contained according to HPLC analysis 42.6 % trans-Voclosporin (further only Voclosporin), 40.2 % cis-Voclosporin and 2.9 % Cyclosporin A. The crude Voclosporin was purified by column chromatography on silica gel using a mixture of toluene and acetone 82 : 18 (v/v) as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated, obtaining purified Voclosporin as a white foam. According to HPLC analysis it contained 85.7 % Voclosporin, 3.6 % cis-Voclosporin and 2.6 % Cyclosporin A (further only purified Voclosporin).

[0096] The Voclosporin crude (containing about 42.6 % of Voclosporin) was used for further optimization of the chromatographic separation of cis-Voclosporin and Voclosporin and the effort resulted in improved process for chromatographic separation which includes purification by column chromatography on silica gel using a mixture of toluene and methylisobutylketone 38 : 62 as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated to a dry residue, weighing 31.0 grams. This residue was not analyzed. The material was dissolved in 25 ml of acetone and then 50 ml of water was added and the solution was let to crystallize for 2 hours in the refrigerator. Then the crystalline product was separated by filtration and dried in vacuum dryer (40 °C, 50 mbar, 12 hours), obtaining 29.6 g of dry product containing 90.6 % of Voclosporin, 0.4 % cis-Voclosporin and 3.7 % Cyclosporin A (further mentioned as final Voclosporin).

Example 1: Preparation of Voclosporin Form A

4.1 grams of Purified Voclosporin was dissolved in acetone and the solution was evaporated to 8.0 grams and the concentrate was diluted by 6 ml of water. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and water 1 : 1 (v/v) and dried on open air obtaining 2.6 grams of crystalline product Form A. Voclosporin form A was confirmed by PXRD as presented in Figure 1.

Example 2: Preparation of Voclosporin Form B

[0097] 1.0 gram of Purified Voclosporin was dissolved in a mixture of 1.5 ml acetone and 3.0 ml n-hexane. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and hexane 1 : 2 (v/v) and dried on open air obtaining 0.5 grams of crystalline product Form B. Voclosporin form B was confirmed by PXRD as presented in Figure 2.

Example 3: Preparation of Amorphous Voclosporin

[0098] 2.0 grams of Purified Voclosporin was dissolved in 40 ml of hot cyclohexane and the solution was stirred for 12 hours at room temperature. Then the crystalline product was filtered off and washed with 5 ml of cyclohexane and dried on open air, obtaining 1.3 grams of amorphous powder. Amorphous Voclosporin was confirmed by PXRD as presented in Figure 3

Example 4: Preparation of Voclosporin Form C

[0099] Final Voclosporin (2 grams) was dissolved in acetonitrile (20 ml) at 50 °C, water (6 ml) was added with stirring, and the clear solution was allowed to crystallize 5 days at 20 °C. Colorless needle crystals were directly mounted to the goniometer head in order to define the crystal structure. Voclosporin form C was confirmed by X-ray crystal structure determination.

References

^ “Luveniq Approval Status”. Luveniq (voclosporin) is a next-generation calcineurin inhibitor intended for the treatment of noninfectious uveitis involving the intermediate or posterior segments of the eye.
^ “What is voclosporin?”. Isotechnika. Retrieved October 19, 2012.
^ U.S. Patent 6,605,593

External links

Voclosporin, ClinicalTrials.gov

Voclosporin
Names

IUPAC name (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-Ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4,6-heptadien-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
Other names VCS, ISA247, Luveniq
Identifiers
CAS Number	515814-01-4
3D model (JSmol)	Interactive image
ChemSpider	5293683
PubChem CID	6918486
InChI [show]
SMILES [show]
Properties
Chemical formula	C₆₃H₁₁₁N₁₁O₁₂
Molar mass	1214.646 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Synthesis

methanol; potassium carbonate;

Reactants can be synthesized in 7 steps.
Synthesis, vol. 44, 1, (2012), p. 63 – 68

Yield:60%

SYN 2

sulfuric acid; tetrahydrofuran;

ISOTECHNIKA INC., WO2004/89960, A2, (2004) 20 ml of THF were added and the reaction mixture was cooled to 0 °C. 2.7 ML (48.69 mmol, 3 equiv. ) of concentrated sulfuric acid were added. The temperature was raised to RT. After completion of the reaction (ca 1 hour), 100 ml of water were added. The organic phase was separated and washed 2 times with 50 ml water. The water phases were re-extracted sequentially with 50 ml dichloromethane. The c ombined organic phases were dried over NA2SO4, filtered and concentrated under reduced pressure at 3 0°C. The resulting white foam was re-dissolved in 250 ml MTBE and after a few minutes, the crystalli zation started. After stirring 15 min. at RT and 2 hours at 0-2 C, THE SUSPENSION WAS FILTERED. THE crystals were washed with 50 ml cold MTBE (-20 °C) and dried at 40-50 °C under reduced pressure to p rovide 19.2 g of (E) -acetyl-ISA247 as white powder in >98percent isomeric purity (400MHZ LH NMR). (E)-ACETYL-ISA247 can be RECRYSTALLIZED by dissolving the solid in dichloromethane at room temperatur e and exchanging the solvent to MTBE (by adding MTBE, concentrating the solution to half its volume under reduced pressure at 40°C and repeating these operation 2 to three times). The solution is cool ed to room temperature and the crystallization then starts within a few minutes. The suspension is s tirred at room temperature for 2h and 30min at 0°C. The crystals of (E) -acetyl-ISA247 are isolated after filtration, washing with MTBE and drying under reduced pressure at 40°C.iii) Peterson eliminat ion The CRUDE-TRIMETHYLSILYALCOHOL diastereomers mixture (11 g, maximum 4.056 mmol) was dissolved in 25 ml THF. 0.679 ml (12.16 mmol, 3 equiv.) concentrated sulfuric were added dropwise maintaining th e temperature between 20 °C and 25 °C. After 2 hours at RT, 50 ml half saturated aqueous NaCl soluti on were added. The resulting mixture was extracted twice with 50 ML MTBE. The organic phases were washed with 50ML of a half saturated aqueous NACL solution, combined, dried over NA2SO4 and concentrat ed under reduce pressure at 40°C. The resulting crude E-acetyl-ISA247 was re-dissolved in 20 ml dich loromethane and concentrated under reduced pressure. The crude product was dissolved in 60 ml MTBE. The crystallization started within 10 min. The suspension was stirred for an additional 15 min. at R T and 2 hours AT-10 °C. The crystals were isolated by filtration, washed with 20 ml cold MTBE (-20 ° C) and dried under reduced pressure to provide 3. 6 G of (E)-ACETYL-ISA247 in ca 98percent isomeric purity by NMR.iii) Peterson elimination After overnight reaction, the organic layer was separated an d the water phase was discarded. 50 ML THF were added to the organic phase. The solution was concent rated under reduced pressure at 30 °C to half its volume. 100 ML THP were added and the solution was concentrated to 80 ML. The volume was adjusted to 100 ml with THF and the solution was cooled to 0- 2 °C. 1. 812 ML (32. 46 MMOL, 2 equiv.) concentrated sulfuric acid were added dropwise over 5 min., maintaining the temperature below 5 °C. After addition, the reaction cooling bath was removed and th e temperature was raised to RT. After 4 hours reaction, 40 ML water were added followed by 20 ml MTB E. The aqueous layer was separated and discarded. The organic phase was washed with 40 ml NAHCO3 Q, 20 ML saturated NACLAQ, 40 ml saturated NaClaq, dried over Na2SO4, filtered and concentrated at 40 ° C under reduced pressure. The crude E-acetyl-ISA247 was RE-DISSOLVED in 200 ml MTBE and crystallizat ion started within a few minutes. After 15 min. at RT and 2.5 hours at 0 °C, the suspension was filt ered, the crystals were washed with 50 ML MTBE and dried at 50 °C under reduced pressure to give 18. 45 g of (E) -acetyl-ISA247 as a white powder (>98percent isomeric purity by NMR).iii) Peterson elim ination 5 ml THF were added to the organic phase and the solution was cooled to 0- 2 °C. 181 UL (3.2 46, 2 equiv. ) concentrated sulfuric acid were added. The reaction mixture was warmed up to RT. Afte r stirring overnight, 20 ml water were added. The aqueous layer was separated and discarded. The organic phase was washed with 20 ml of 5percent aqueous NAHCO3 solution, dried over MGS04, filtered and concentrated under reduced pressure at 40 °C to give 2 g of (E) -acetyl-ISA247 as a white foam in > 98percent double bond isomeric purity (by NMR).ii) Peterson elimination The crude product was dissol ved in 11.15 ML THF and 268 P1 concentrated sulfuric acid were added. The reaction mixture was heate d at 33 °C for 1.5 hour and then cooled to RT. 22 ml water were added and the reaction mixture was e xtracted with 22 ml MTBE. The aqueous phase was RE-EXTRACTED with 11 ml MTBE. The organic layer were washed with 11 ml water, combined, dried over NA2SO4, filtered and concentrated at 40 °C under redu ced pressure to give 1.89 g of crude (E) -acetyl-ISA247 as a beige powder. The crude product was re-dissolved in 20 ml MTBE at RT. The crystallization started within a few minutes. The suspension was stirred 30 min. at RT, 45 min. at-10 °C and was filtered. The solid was washed with cold MTBE and dr ied at 40 °C under reduced pressure to give 1.02 g of (E)-acetylISA247 as a white powder in ca 98per cent double bond isomeric purity (NMR). ii) Peterson elimination The crude product was dissolved in 8 ML THF at RT. The solution was cooled to 0-5 °C and 200 UL of concentrated sulfuric acid were adde d dropwise. The temperature was raised to RT and the reaction mixture was stirred 10 hours. 40 ml MTBE and 15 ml of water were added. The water phase was separated and discarded. The organic phase was washed 15 ml of a 5percent aqueous NAHCO3 solution, 15 ml of a half saturated aqueous NACL solution, dried over NA2SO4, filtered and concentrated under reduced pressure to give 1. 8 g of crude E-acet yl- ISA247. The crude diene was dissolved in 20 ml dichloromethane. 20 ML MTBE were added, and the s olution was concentrated at 40 °C under reduced pressure to half its volume. The last two operations was repeated three times to in order to exchange the solvent from dichloromethane to MTBE. The solution was cooled to RT and the crystallization started within a few minutes. The suspension was stirr ed 2 hours at RT and 30 min. at 0 °C. The suspension was filtered. The solid was washed with 15 ml M TBE and dried under reduced pressure at 40 °C to give 1.1 g OF E-ACETYL-ISA247 in >95percent double bond isomeric purity (NMR), as a white powder.ii) Peterson elimination The crude product was dissolv ed in 10 ml THF at RT. The solution was cooled to 0-5 °C and 200 UL of concentrated sulfuric acid we re added dropwise. The temperature was raised to RT and the reaction mixture was stirred overnight. 40 ml MTBE and 15 ML of water were added. The water phase was separated and discarded. The organic p hase was washed with 15 ml water, 15 ml of a 5percent aqueous NAHCO3 solution, 15 ml of a half saturated aqueous NaCl solution, filtered and concentrated under reduced pressure to give 1.8 g of crude E-ACETYL-ISA247. The crude diene was redissolved in 35 ml of MTBE. The crystallization started withi n a few minutes. The suspension was stirred 2 hours at RT and 30 min. at 0 °C. The suspension was fi ltered. The solid was washed with 15 ml MTBE and dried under reduced pressure at 40 °C to gi ve 1 g of E-acetyl-ISA247 in >95percent double bond isomeric purity (NMR), as a white powder.

REFERENCES

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2: Dang W, Yin Y, Wang Y, Wang W, Su J, Sprengers D, van der Laan LJW, Felczak K, Pankiewicz KW, Chang KO, Koopmans MPG, Metselaar HJ, Peppelenbosch MP, Pan Q. Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e01095-17. doi: 10.1128/AAC.01095-17. Print 2017 Nov. PubMed PMID: 28807916; PubMed Central PMCID: PMC5655111.

3: Wong TC, Lo CM, Fung JY. Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation. Expert Opin Emerg Drugs. 2017 Jun;22(2):123-136. doi: 10.1080/14728214.2017.1330884. Epub 2017 May 22. Review. PubMed PMID: 28503959.

4: Chow C, Simpson MJ, Luger TA, Chubb H, Ellis CN. Comparison of three methods for measuring psoriasis severity in clinical studies (Part 1 of 2): change during therapy in Psoriasis Area and Severity Index, Static Physician’s Global Assessment and Lattice System Physician’s Global Assessment. J Eur Acad Dermatol Venereol. 2015 Jul;29(7):1406-14. doi: 10.1111/jdv.13132. Epub 2015 Apr 27. PubMed PMID: 25917315.

5: Simpson MJ, Chow C, Morgenstern H, Luger TA, Ellis CN. Comparison of three methods for measuring psoriasis severity in clinical studies (Part 2 of 2): use of quality of life to assess construct validity of the Lattice System Physician’s Global Assessment, Psoriasis Area and Severity Index and Static Physician’s Global Assessment. J Eur Acad Dermatol Venereol. 2015 Jul;29(7):1415-20. doi: 10.1111/jdv.12861. Epub 2015 Apr 27. PubMed PMID: 25917214.

6: Maya JR, Sadiq MA, Zapata LJ, Hanout M, Sarwar S, Rajagopalan N, Guinn KE, Sepah YJ, Nguyen QD. Emerging therapies for noninfectious uveitis: what may be coming to the clinics. J Ophthalmol. 2014;2014:310329. doi: 10.1155/2014/310329. Epub 2014 Apr 24. Review. PubMed PMID: 24868451; PubMed Central PMCID: PMC4020293.

7: Hardinger KL, Brennan DC. Novel immunosuppressive agents in kidney transplantation. World J Transplant. 2013 Dec 24;3(4):68-77. doi: 10.5500/wjt.v3.i4.68. Review. PubMed PMID: 24392311; PubMed Central PMCID: PMC3879526.

8: Ling SY, Huizinga RB, Mayo PR, Larouche R, Freitag DG, Aspeslet LJ, Foster RT. Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin. Br J Clin Pharmacol. 2014 Jun;77(6):1039-50. doi: 10.1111/bcp.12309. PubMed PMID: 24330024; PubMed Central PMCID: PMC4093929.

9: Mayo PR, Ling SY, Huizinga RB, Freitag DG, Aspeslet LJ, Foster RT. Population PKPD of voclosporin in renal allograft patients. J Clin Pharmacol. 2014 May;54(5):537-45. doi: 10.1002/jcph.237. Epub 2013 Nov 30. PubMed PMID: 24243422.

10: Gubskaya AV, Khan IJ, Valenzuela LM, Lisnyak YV, Kohn J. Investigating the Release of a Hydrophobic Peptide from Matrices of Biodegradable Polymers: An Integrated Method Approach. Polymer (Guildf). 2013 Jul 8;54(15):3806-3820. PubMed PMID: 24039300; PubMed Central PMCID: PMC3770487.

11: Ling SY, Huizinga RB, Mayo PR, Freitag DG, Aspeslet LJ, Foster RT. Pharmacokinetics of voclosporin in renal impairment and hepatic impairment. J Clin Pharmacol. 2013 Dec;53(12):1303-12. doi: 10.1002/jcph.166. Epub 2013 Oct 8. PubMed PMID: 23996158.

12: Mayo PR, Huizinga RB, Ling SY, Freitag DG, Aspeslet LJ, Foster RT. Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects. J Clin Pharmacol. 2013 Aug;53(8):819-26. doi: 10.1002/jcph.114. Epub 2013 Jun 4. PubMed PMID: 23736966.

13: Schultz C. Voclosporin as a treatment for noninfectious uveitis. Ophthalmol Eye Dis. 2013 May 5;5:5-10. doi: 10.4137/OED.S7995. Print 2013. PubMed PMID: 23700374; PubMed Central PMCID: PMC3653814.

14: Gomes Bittencourt M, Sepah YJ, Do DV, Agbedia O, Akhtar A, Liu H, Akhlaq A, Annam R, Ibrahim M, Nguyen QD. New treatment options for noninfectious uveitis. Dev Ophthalmol. 2012;51:134-61. doi: 10.1159/000336338. Epub 2012 Apr 17. Review. PubMed PMID: 22517211.

15: Khan IJ, Murthy NS, Kohn J. Hydration-induced phase separation in amphiphilic polymer matrices and its influence on voclosporin release. J Funct Biomater. 2012 Oct 30;3(4):745-59. doi: 10.3390/jfb3040745. PubMed PMID: 24955746; PubMed Central PMCID: PMC4030927.

16: Roesel M, Tappeiner C, Heiligenhaus A, Heinz C. Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis. Clin Ophthalmol. 2011;5:1309-13. doi: 10.2147/OPTH.S11125. Epub 2011 Sep 13. PubMed PMID: 21966207; PubMed Central PMCID: PMC3180504.

17: Busque S, Cantarovich M, Mulgaonkar S, Gaston R, Gaber AO, Mayo PR, Ling S, Huizinga RB, Meier-Kriesche HU; PROMISE Investigators. The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant. 2011 Dec;11(12):2675-84. doi: 10.1111/j.1600-6143.2011.03763.x. Epub 2011 Sep 22. PubMed PMID: 21943027.

18: Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, Benz J, Aspeslet L, Freitag D, Hennig M. Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr. 2011 Feb;67(Pt 2):119-23. doi: 10.1107/S0907444910051905. Epub 2011 Jan 15. PubMed PMID: 21245533; PubMed Central PMCID: PMC3045272.

19: Kunynetz R, Carey W, Thomas R, Toth D, Trafford T, Vender R. Quality of life in plaque psoriasis patients treated with voclosporin: a Canadian phase III, randomized, multicenter, double-blind, placebo-controlled study. Eur J Dermatol. 2011 Jan-Feb;21(1):89-94. doi: 10.1684/ejd.2010.1185. PubMed PMID: 21227890.

20: Deuter CM. [Systemic voclosporin for uveitis treatment]. Ophthalmologe. 2010 Jul;107(7):672-5. doi: 10.1007/s00347-010-2217-5. German. PubMed PMID: 20571806.

//////////VOCLOSPORIN, Voclosporin, ISA247, ISAtx 247, ISAtx-247, ISAtx247, Luveniq, LX211,

CC[C@@H]1NC([C@@H](N(C([C@@H](N(C([C@@H](N(C([C@@H](N(C([C@H](NC([C@@H](NC([C@@H](N(C([C@H](C(C)C)NC([C@@H](N(C(CN(C1=O)C)=O)C)CC(C)C)=O)=O)C)CC(C)C)=O)C)=O)C)=O)C)CC(C)C)=O)C)CC(C)C)=O)C)C(C)C)=O)C)[C@@H]([C@@H](C/C=C/C=C)C)O)=O

AZITHROMYCIN, アジスロマイシン;

March 29, 2020 3:32 am / 1 Comment on AZITHROMYCIN, アジスロマイシン;

Azithromycin

ChemSpider 2D Image | Azithromycin | C38H72N2O12

AZITHROMYCIN

C38H72N2O12,

748.9845

アジスロマイシン;

CAS:	83905-01-5

PubChem:

ChEBI:

ChEMBL:

DrugBank:

PDB-CCD:

ZIT[PDBj]

LigandBox:

D07486

NIKKAJI:

J134.080H

CAS Registry Number: 83905-01-5

CAS Name: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-a-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one

Additional Names: N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A

Molecular Formula: C38H72N2O12

Molecular Weight: 748.98

Percent Composition: C 60.94%, H 9.69%, N 3.74%, O 25.63%

Literature References: Semi-synthetic macrolide antibiotic; related to erythromycin A, q.v. Prepn: BE 892357; G. Kobrehel, S. Djokic, US 4517359 (1982, 1985 both to Sour Pliva); of the crystalline dihydrate: D. J. M. Allen, K. M. Nepveux, EP 298650; eidem, US 6268489 (1989, 2001 both to Pfizer). Antibacterial spectrum: S. C. Aronoff et al., J. Antimicrob. Chemother. 19, 275 (1987); and mode of action: J. Retsema et al., Antimicrob. Agents Chemother. 31, 1939 (1987). Series of articles on pharmacology, pharmacokinetics, and clinical experience: J. Antimicrob. Chemother. 31, Suppl. E, 1-198 (1993). Clinical trial in prevention of Pneumocystis carinii pneumonia in AIDS patients: M. W. Dunne et al., Lancet 354, 891 (1999). Review of pharmacology and clinical efficacy in pediatric infections: H. D. Langtry, J. A. Balfour, Drugs 56, 273-297 (1998).

Properties: Amorphous solid, mp 113-115°. [a]D20 -37° (c = 1 in CHCl3).

Melting point: mp 113-115°

Optical Rotation: [a]D20 -37° (c = 1 in CHCl3)

Derivative Type: Dihydrate

CAS Registry Number: 117772-70-0

Manufacturers’ Codes: CP-62993; XZ-450

Trademarks: Azitrocin (Pfizer); Ribotrex (Fabre); Sumamed (Pliva); Trozocina (Sigma-Tau); Zithromax (Pfizer); Zitromax (Pfizer)

Properties: White crystalline powder. mp 126°. [a]D26 -41.4° (c = 1 in CHCl3).

Melting point: mp 126°

Optical Rotation: [a]D26 -41.4° (c = 1 in CHCl3)

Therap-Cat: Antibacterial.

Azithromycin is an antibiotic used for the treatment of a number of bacterial infections.^[3] This includes middle ear infections, strep throat, pneumonia, traveler’s diarrhea, and certain other intestinal infections.^[3] It can also be used for a number of sexually transmitted infections, including chlamydia and gonorrhea infections.^[3] Along with other medications, it may also be used for malaria.^[3] It can be taken by mouth or intravenously with doses once per day.^[3]

Common side effects include nausea, vomiting, diarrhea and upset stomach.^[3] An allergic reaction, such as anaphylaxis, QT prolongation, or a type of diarrhea caused by Clostridium difficile is possible.^[3] No harm has been found with its use during pregnancy.^[3] Its safety during breastfeeding is not confirmed, but it is likely safe.^[4] Azithromycin is an azalide, a type of macrolide antibiotic.^[3] It works by decreasing the production of protein, thereby stopping bacterial growth.^[3]

Azithromycin was discovered 1980 by Pliva, and approved for medical use in 1988.^[5]^[6] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[7] The World Health Organization classifies it as critically important for human medicine.^[8] It is available as a generic medication^[9] and is sold under many trade names worldwide.^[2] The wholesale cost in the developing world is about US$0.18 to US$2.98 per dose.^[10] In the United States, it is about US$4 for a course of treatment as of 2018.^[11] In 2016, it was the 49th most prescribed medication in the United States with more than 15 million prescriptions.^[12]

Medical uses

Azithromycin is used to treat many different infections, including:

Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.^[13]
Community-acquired pneumonia due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae^[14]
Uncomplicated skin infections due to S. aureus, S. pyogenes, or S. agalactiae
Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.^[15]
Trachoma due to C. trachomatis^[16]
Genital ulcer disease (chancroid) in men due to H. ducrey
Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.^[17]^[18]
Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.^[19]
Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy^[20]

Bacterial susceptibility

Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.

A strain of gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin,^[21] but the drug is not widely used as monotherapy due to a low barrier to resistance development.^[15] Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.^[22]

Aerobic and facultative Gram-positive microorganisms

Staphylococcus aureus (Methicillin-sensitive only)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

Aerobic and facultative Gram-negative microorganisms

Anaerobic microorganisms

Peptostreptococcus species
Prevotella bivia

Other microorganisms

Pregnancy and breastfeeding

No harm has been found with use during pregnancy.^[3] However, there are no adequate well-controlled studies in pregnant women.^[23]

Safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects.^[4] Nevertheless, it is recommended that the drug be used with caution during breastfeeding.^[3]

Airway diseases

Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes.^[24] And potentially useful in asthma and sinusitis via this mechanism.^[25] Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.^[26]^[27]

Adverse effects

Most common adverse effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, skin reactions, and anaphylaxis have been reported.^[28] Clostridium difficile infection has been reported with use of azithromycin.^[3] Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.^[29]

Occasionally, people have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.^[30]^[31]

In 2013 the FDA issued a warning that azithromycin “can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.” The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.^[32]^[33]^[34]

Pharmacology

Mechanism of action

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.^[23]

Pharmacokinetics

Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (T_max) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility.^{[citation needed]} Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.^[35]

Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours.^[35] Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.

History

A team of researchers at the pharmaceutical company Pliva in Zagreb, SR Croatia, Yugoslavia, — Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Dr. Slobodan Đokić — discovered azithromycin in 1980.^[6] It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva’s license in other markets under the brand name Zithromax in 1991.^[36] Patent protection ended in 2005.^[37]

Society and culture

Zithromax (azithromycin) 250 mg tablets (CA)

Cost

It is available as a generic medication.^[9] The wholesale cost is about US$0.18 to US$2.98 per dose.^[10] In the United States it is about US$4 for a course of treatment as of 2018.^[11] In India, it is about US$1.70 for a course of treatment.^{[citation needed]}

Available forms

Azithromycin is commonly administered in film-coated tablet, capsule, oral suspension, intravenous injection, granules for suspension in sachet, and ophthalmic solution.^[2]

Usage

In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US,^[38] whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.^[39]

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References

^ Jump up to:^a ^b “Azithromycin Use During Pregnancy”. Drugs.com. 2 May 2019. Retrieved 24 December 2019.
^ Jump up to:^a ^b ^c ^d ^e ^f “Azithromycin International Brands”. Drugs.com. Archived from the original on 28 February 2017. Retrieved 27 February 2017.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “Azithromycin”. The American Society of Health-System Pharmacists. Archived from the original on 5 September 2015. Retrieved 1 August 2015.
^ Jump up to:^a ^b “Azithromycin use while Breastfeeding”. Archived from the original on 5 September 2015. Retrieved 4 September 2015.
^ Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1. publ. ed.). Oxford: Oxford University Press. p. 239. ISBN 9780199534845. Archived from the original on 5 March 2016.
^ Jump up to:^a ^b Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 498. ISBN 9783527607495.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266. ISBN 9789241515528. License: CC BY-NC-SA 3.0 IGO.
^ Jump up to:^a ^b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. ISBN 9781284057560.
^ Jump up to:^a ^b “Azithromycin”. International Drug Price Indicator Guide. Retrieved 4 September 2015.
^ Jump up to:^a ^b “NADAC as of 2018-05-23”. Centers for Medicare and Medicaid Services. Retrieved 24 May 2018.
^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December2018.
^ Taylor SP, Sellers E, Taylor BT (2015). “Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly”. Am. J. Med. 128 (12): 1362.e1–6. doi:10.1016/j.amjmed.2015.07.032. PMID 26291905.
^ Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG (2007). “Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults”. Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159. PMID 17278083.
^ Jump up to:^a ^b “Gonococcal Infections – 2015 STD Treatment Guidelines”. Archived from the original on 1 March 2016.
^ Burton M, Habtamu E, Ho D, Gower EW (2015). “Interventions for trachoma trichiasis”. Cochrane Database Syst Rev. 11 (11): CD004008. doi:10.1002/14651858.CD004008.pub3. PMC4661324. PMID 26568232.
^ Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, Orlandi RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015). “Clinical practice guideline (update): adult sinusitis”. Otolaryngol Head Neck Surg. 152 (2 Suppl): S1–S39. doi:10.1177/0194599815572097. PMID 25832968.
^ Hauk L (2014). “AAP releases guideline on diagnosis and management of acute bacterial sinusitis in children one to 18 years of age”. Am Fam Physician. 89 (8): 676–81. PMID 24784128.
^ Neff MJ (2004). “AAP, AAFP release guideline on diagnosis and management of acute otitis media”. Am Fam Physician. 69 (11): 2713–5. PMID 15202704.
^ Randel A (2013). “IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis”. Am Fam Physician. 88 (5): 338–40. PMID 24010402.
^ The Guardian newspaper: ‘Super-gonorrhoea’ outbreak in Leeds, 18 September 2015 Archived 18 September 2015 at the Wayback Machine
^ Lippincott Illustrated Reviews : Pharmacology Sixth Edition. p. 506.
^ Jump up to:^a ^b “US azithromycin label”(PDF). FDA. February 2016. Archived(PDF) from the original on 23 November 2016.
^ Simoens, Steven; Laekeman, Gert; Decramer, Marc (May 2013). “Preventing COPD exacerbations with macrolides: A review and budget impact analysis”. Respiratory Medicine. 107 (5): 637–648. doi:10.1016/j.rmed.2012.12.019. PMID 23352223.
^ Gotfried, Mark H. (February 2004). “Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD”. CHEST. 125 (2): 52S–61S. doi:10.1378/chest.125.2_suppl.52S. ISSN 0012-3692. PMID 14872001.
^ Zarogoulidis, P.; Papanas, N.; Kioumis, I.; Chatzaki, E.; Maltezos, E.; Zarogoulidis, K. (May 2012). “Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases”. European Journal of Clinical Pharmacology. 68 (5): 479–503. doi:10.1007/s00228-011-1161-x. ISSN 1432-1041. PMID 22105373.
^ Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles (2012). “Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics”. Mediators of Inflammation. 2012: 584262. doi:10.1155/2012/584262. PMC3388425. PMID 22778497.
^ Mori F, Pecorari L, Pantano S, Rossi M, Pucci N, De Martino M, Novembre E (2014). “Azithromycin anaphylaxis in children”. Int J Immunopathol Pharmacol. 27 (1): 121–6. doi:10.1177/039463201402700116. PMID 24674687.
^ Dart, Richard C. (2004). Medical Toxology. Lippincott Williams & Wilkins. p. 23.
^ Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). “Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose”. Pharmacotherapy. 26 (1): 147–50. doi:10.1592/phco.2006.26.1.147. PMID 16506357.
^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133.
^ Denise Grady (16 May 2012). “Popular Antibiotic May Raise Risk of Sudden Death”. The New York Times. Archived from the original on 17 May 2012. Retrieved 18 May 2012.
^ Ray, Wayne A.; Murray, Katherine T.; Hall, Kathi; Arbogast, Patrick G.; Stein, C. Michael (2012). “Azithromycin and the Risk of Cardiovascular Death”. New England Journal of Medicine. 366(20): 1881–90. doi:10.1056/NEJMoa1003833. PMC3374857. PMID 22591294.
^ “FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms”. FDA. 12 March 2013. Archived from the original on 27 October 2016.
^ Jump up to:^a ^b “Archived copy”. Archived from the original on 14 October 2014. Retrieved 10 October 2014.
^ Banić Tomišić, Z. (2011). “The Story of Azithromycin”. Kemija U Industriji. 60 (12): 603–617. ISSN 0022-9830. Archived from the original on 8 September 2017.
^ “Azithromycin: A world best-selling Antibiotic”. http://www.wipo.int. World Intellectual Property Organization. Retrieved 18 June 2019.
^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (April 2013). “U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 368 (15): 1461–1462. doi:10.1056/NEJMc1212055. PMID 23574140.
^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (September 2013). “More on U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 369 (12): 1175–1176. doi:10.1056/NEJMc1306863. PMID 24047077.

External links

Keywords: Antibacterial (Antibiotics); Macrolides.

“Azithromycin”. Drug Information Portal. U.S. National Library of Medicine.

Azithromycin
Clinical data


Trade names	Zithromax, Azithrocin, others^[2]
Other names	9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A
AHFS/Drugs.com	Monograph
MedlinePlus	a697037
License data	EU EMA: by INN US DailyMed: Azithromycin US FDA: Azithromycin
Pregnancy category	AU: B1 ^[1] US: B (No risk in non-human studies) ^[1]
Routes of administration	By mouth (capsule, tablet or suspension), intravenous, eye drop
Drug class	Macrolide antibiotic
ATC code	J01FA10 (WHO) S01AA26 (WHO) J01RA07 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	38% for 250 mg capsules
Metabolism	Liver
Elimination half-life	11–14 h (single dose) 68 h (multiple dosing)
Excretion	Biliary, kidney (4.5%)
Identifiers
IUPAC name [show]
CAS Number	83905-01-5
PubChem CID	55185
IUPHAR/BPS	6510
DrugBank	DB00207
ChemSpider	10482163
UNII	J2KLZ20U1M
KEGG	D07486
ChEBI	CHEBI:2955
ChEMBL	ChEMBL529
NIAID ChemDB	007311
CompTox Dashboard (EPA)	DTXSID8030760
ECHA InfoCard	100.126.551
Chemical and physical data
Formula	C₃₈H₇₂N₂O₁₂
Molar mass	748.984 g·mol⁻¹ g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CN(C)[C@H]3C[C@@H](C)O[C@@H](O[C@@H]2[C@@H](C)[C@H](O[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1)[C@@H](C)C(=O)O[C@H](CC)[C@@](C)(O)[C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@]2(C)O)[C@@H]3O

/////////AZITHROMYCIN, Antibacterial, Antibiotics, Macrolides, CORONA VIRUS, COVID 19, アジスロマイシン ,

Substances Referenced in Synthesis Path
CAS-RN Formula Chemical Name CAS Index Name
76801-85-9 C37H70N2O12 2-deoxo-9a-aza-9a-homoerythromycin A 1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-eth- yl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-, [2R-(2
R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,13S*,1
4R*)]-

90503-04-1 C37H70N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
13S*,14R*)]-13-[(2,6-dideoxy-3-C-methyl3-O-methyl-α-L-ribo-hexopyranosyl)
oxy]-2-ethyl-3,4,6,10-tetrahydroxy3,5,8,10,12,14-hexamethyl-13-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-
β-D-xylo-hexopyranosyl] oxy]-1-oxa-6-azacyclopentadecan-15-one
1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-Omethyl-α-L-ribo-hexopyranosyl)
oxy]-2-ethyl-3,4,6,10-tetrahydroxy3,5,8,10,12,14-hexamethyl-13-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-β-Dxylo-hexopyranosyl]oxy]-, [2R-(2R*,3S*,4R
*,5R*,8R*,10R*,11R*,12S*,13S*,14R*)]-

90503-05-2 C38H72N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
13S*,14R*)]-13-[(2,6-dideoxy-3-C-methyl3-O-methyl-α-L-ribo-hexopyranosyl) oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-
β-D-xylo-hexopyranosyl]
oxy]-1-oxa-6-azacyclopentadecan-15-one
6-oxide
1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-Omethyl-α-L-ribo-hexopyranosyl)
oxy]-2-ethyl-3,4,10-trihydroxy3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-
trideoxy-3-(dimethyloxidoamino)-βD-xylo-hexopyranosyl]oxy]-, 6-oxide,
[2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,1
3S*,14R*)]-

50-00-0 CH2O formaldehyde Formaldehyde
74-88-4 CH3I methyl iodide Methane, iodoTrade Names

Country Trade Name Vendor Annotation
D Ultreon Pfizer
Zithromax Pfizer Pharma/Gödecke/Parke-Davis
numerous generic preparations
F Azadose Pfizer
Monodose Pfizer
Zithromax Pfizer
GB Zithromax Pfizer
I Azitrocin Bioindustria
Ribotrex Pierre Fabre
Trocozina Sigma-Tau
Zithromax Pfizer
J Zithromac Pfizer
USA Azasite InSite Vision
Zithromax Pfizer as dihydrate

Formulations
cps. 100 mg, 250 mg; Gran. 10%; susp. 200 mg (as dihydrate); tabl. 250 mg
References
Djokic, S. et al.: J. Antibiot. (JANTAJ) 40, 1006 (1987).
a DOS 3 140 449 (Pliva; appl. 12.10.1981; YU-prior. 6.3.1981).
US 4 517 359 (Pliva; 14.5.1985; appl. 22.9.1981; YU-prior. 6.3.1981).
b EP 101 186 (Pliva; appl. 14.7.1983; USA-prior. 19.7.1982, 15.11.1982).
US 4 474 768 (Pfizer; 2.10.1984; prior. 19.7.1982, 15.11.1982).
educt by ring expansion of erythromycin A oxime by Beckmann rearrangement:
Djokic, S. et al.: J. Chem. Soc., Perkin Trans. 1 (JCPRB4) 1986, 1881-1890.
Bright, G.M. et al.: J. Antibiot. (JANTAJ) 41, 1029 (1988). US 4 328 334 (Pliva; 4.5.1982; YU-prior. 2.4.1979).
stable, non-hygroscopic dihydrate: EP 298 650 (Pfizer; appl. 28.6.1988).
medical use for treatment of protozoal infections:
US 4 963 531 (Pfizer; 16.10.1990; prior. 16.8.1988, 10.9.1987).

Molnupiravir, EIDD 2801

March 28, 2020 3:49 am / 7 Comments on Molnupiravir, EIDD 2801

CID 145996610.png

EIDD 2801

Molecular Formula:	C₁₃H₁₉N₃O₇
Molecular Weight:	329.31 g/mol

[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl 2-methylpropanoate

UNII YA84KI1VEW

CAS 2349386-89-4

Molnupiravir (development codes MK-4482 and EIDD-2801) is an experimental antiviral drug which is orally active (can be taken orally) and was developed for the treatment of influenza. It is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, and exerts its antiviral action through introduction of copying errors during viral RNA replication.^[1]^[2] Activity has also been demonstrated against coronaviruses including SARS, MERS and SARS-CoV-2.^[3]

The drug was developed at Emory University by the university’s drug innovation company, Drug Innovation Ventures at Emory (DRIVE). It was then acquired by Miami-based company Ridgeback Biotherapeutics, who later partnered with Merck & Co. to develop the drug further.

Safety Controversy

In April 2020, a whistleblower complaint by former Head of US Biomedical Advanced Research and Development Authority (BARDA) Rick Bright revealed concerns over providing funding for the further development of molnupiravir due to similar drugs having mutagenic properties (producing birth defects).^[4] A previous company, Pharmasset, that had investigated the drug’s active ingredient had abandoned it. These claims were denied by George Painter, CEO of DRIVE, noting that toxicity studies on molnupiravir had been carried out and data provided to regulators in the US and UK, who permitted safety studies in humans to move forward in the spring of 2020. Also at this time, DRIVE and Ridgeback Biotherapeutics stated they planned future safety studies in animals.^[5]

COVID-19

After being found to be active against SARS-CoV-2 in March 2020, molnupiravir was tested in a preliminary human study for “Safety, Tolerability, and Pharmacokinetics” in healthy volunteers in the UK and US.^[6] In June 2020, Ridgeback Biotherapeutics announced it was moving to Phase II trials to test the efficacy of the drug as a treatment for COVID-19.^[7] Two trials of small numbers of hospitalized and non-hospitalized patients in the US and the UK were underway in July.^[8]^[9] In late July 2020, and without yet releasing any medical data, Merck, which had been partnering with Ridgeback Biotherapeutics on developing the drug, announced its intention to move molnupiravir to late stage trials beginning in September 2020.^[10] On October 19 2020, Merck began a one year Stage 2/3 trial focused on hospitalized patients.^[11]

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PATENT

WO 2019113462

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019113462

Example 10: Synthesis of EIDD-2801

A 1L round bottom flask was charged with uridine (25 g, 102.38 mmol) and acetone (700 mL). The reaction mixture was allowed to stir at rt. The slurry was then treated with sulfuric acid (0.27 mL, 5.12 mmol). Stirring was allowed to continue at rt for 18 hours. The reaction was quenched with 100 mL of trimethylamine and was used in the next step without further pruficication.

A 1L round bottom flask was charged with the reaction mixture from the previous reaction. Triethylamine (71.09 mL, 510.08 mmol) and 4-dimethylaminopyridine (0.62 g, 5.1 mmol) were then added. The flask was cooled using an ice bath and then 2-methylpropanoyl 2-methylpropanoate (17.75 g, 112.22 mmol) was slowly added. The reaction mixture was allowed to stir at rt until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 600 mL ethyl acetate and washed with saturated aqueous bicarbonate solution x 2, water x 2 and brine x 2. The organics were dried over sodium sulfate and concentrated under reduced pressure to yield a clear colorless oil. The crude product was used in the next step without further purification.

A 1L round bottom flask was charged with the crude product from above (36 g, 101.59 mmol) and MeCN (406.37 mL). The reaction mixture was allowed to stir until all the starting material was dissolved. Next, 1,2, 4-triazole (50.52 g, 731.46 mmol) was added followed by the addition of N,N-diethylethanamine (113.28 mL, 812.73 mmol). The reaction mixture was allowed to stir at rt until all solids dissolved. The reaction was then cooled to 0°C using an ice bath. Phosphorous oxychloride (24.44 mL, 152.39 mmol) was added slowly. The slurry that formed was allowed to stir under argon while slowly warming to rt. The reaction was then allowed to stir until complete by TLC (EtOAc). The reaction was then quenched by the addition of lOOmL of water. The slurry then became a dark colored solution, which was

then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (2 x 330 g columns). All fractions containing product were collected and concentrated under reduced pressure.

A 500 mL round bottom flask was charged with the product from the previous step (11.8 g, 29.11 mmol) and isopropyl alcohol (150 mL). The reaction mixture was allowed to stir at rt until all solids dissolved. Next, hydroxylamine (1.34 mL, 43.66 mmol) was added and stirring continued at ambient temperature. When the reaction was complete (HPLC) some solvent was removed under high vacuum at ambient temperature. The remaining solvent was removed under reduced pressure at 45°C. The resulting residue was dissolved in EtOAc and was washed with water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield oil. Crystals formed upon standing at rt. The crystals were collected by filtration, washed with ether x 3, and dried in vacuo to provide the product as a white solid.

A 200 mL round bottom flask was charged with the product from the previous step (6.5 g, 17.6 mmol) and formic acid (100 mL, 2085.6 mmol). The reaction mixture was allowed to stir at rt overnight. The progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under reduced pressure at 42°C to yield a clear, pale pink oil. Next, 30 mL of ethanol was added. Solvent was then removed under reduced pressure. MTBE (50 mL) was added to the solid and heated. Next, isopropyl alcohol was added and heating was continued until all solid material dissolved (5 mL). The solution was then allowed to cool and stand at rt.

A solid started to form after about lhr. The solids were collected by filtration, washed with MTBE, and dried in vacuo to yield the EIDD-2801 as a white solid. The filtrate was concentrated under reduced pressure to yield a sticky solid, which was dissolved in a small amount of isopropyl alcohol with heating. The solution was allowed to stand at rt overnight. A solid formed in the flask, which was collected by filtration, rinsed with isopropyl alcohol and MTBE, and dried in vacuo to an additional crop of desired product.

EIDD-2801 (25 g) was dissolved in 250 mL of isopropyl alcohol by heating to 70°C to give a clear solution. The warm solution was polish filtered and filtrate transferred to 2L three neck flask with overhead stirrer. It was warmed back to 70°C and MTBE (250 mL) was slowly added into the flask. The clear solution was seeded and allowed to cool slowly to rt with stirring for 18 hrs. The EIDD-2801 solid that formed was filtered and washed with MTBE and dried at 50°C under vacuum for l8hours. The filtrate was concentrated, redissolved in 50 mL isopropyl alcohol and 40 mL MTBE by warming to give clear solution and allowed to stand at rt to give a second crop of EIDD-2801.

Example 11: General synthesis for Deuteration

389 390

The lactone 389 (0.0325 mol) was added to a dry flask under an argon atmosphere and was then dissolved in dry THF (250 mL). The solution as then cooled to -78°C and a DIBAL-D solution in toluene (0.065 mol) was dropwise. The reaction was allowed to stir at -78°C for 3-4 hours. The reaction was then quenched with the slow addition of water (3 mL). The reaction was then allowed to stir while warming to rt. The mixture was then diluted with two volumes of diethyl ether and was then poured into an equal volume of saturated sodium potassium tartrate solution. The organic layer was separated, dried over MgSCri. filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with hexanes/ethyl acetate. The resulting lactol 390 was then converted to an acetate or benzolyate and subjected to cytosine coupling conditions and then further elaborated to N-hydroxycytidine.

PATENT

WO 2019173602

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019173602

PAPER

ChemRxiv (2020), 1-3.

AND

ChemRxiv (2020), 1-2

PAPER

A Concise Route to MK-4482 (EIDD-2801) from Cytidine: Part 2
Synlett (2020), Ahead of Print.

https://www.thieme-connect.de/media/synlett/EFirst/supmat/sup_st-2020-v0498-l_10-1055_a-1275-2848.pdf

A new route to MK-4482 was developed. The route replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for the chemical transformations, and the yield is improved from 17% to 44%. A step is removed from the longest linear sequence, and these advancements are expected to expand access to MK-4482 should it become a viable drug substance.

To a 20 mL vial was added N-hydroxycytidine acetonide ester 5 (0.25 g, 96% purity) followed by formic acid (4 mL). The resultant solution was stirred at room temperature for 4 h 20 min. Solvent was removed under reduced pressure and fresh EtOH (5 mL) was added. The resultant solution was again concentrated under vacuum to afford an oil. Methyl tert-butyl ether and IPA (5 mL each) were successively added as described earlier for preparation of compound 4 and concentrated to give 0.205 g of crude material (77% assay yield, 79% purity). This material was purified by silica gel column chromatography in 8 % MeOH/ Chloroform to afford 130 mg of EIDD-2801 as a solid (60% isolated yield corrected for purity, 98% purity) 1H NMR (600 MHz, CD3OD): δ 6.91 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 4.8 Hz, 1H), 5.61 (d, J = 8.2 Hz, 1H), 4.29 (d, J = 3.6 Hz, 2H), 4.14 (t, J = 4.9 Hz, 1H), 4.08 (p, J = 4.9 Hz, 2H), 2.62 (septet, J = 7.0 Hz, 1H), 1.19 (d, J = 7.0 Hz, 6H); 13C NMR (151 MHz, CD3OD): δ 178.6, 151.81, 146.44, 132.04, 99.84, 90.74, 82.88, 74.67, 71.80, 65.23, 35.45, 27.49, 19.65, 19.61.

One-Pot Transamination/Deprotection of 4 to EIDD-2801: To acetonide ester 4 (1.03 g, 77% Purity) in a 100 mL single neck round bottom flask was added hydroxylamine sulfate (1.09 g, 3.2 equiv.) followed by 40% IPA (20 mL prepared by mixing 12 mL of water and 8 mL of 99.5% IPA. The resultant solution was heated to 78˚C (internal temperature 72-73 ˚C) for 23 h upon which time HPLC showed the formation of EIDD-2801. Solvent was removed on a rotary evaporator and isopropanol (20 mL) was then added. The resulting slurry was sonicated for 5 minutes. The insoluble residue was then filtered and the filtrate concentrated under reduced pressure to afford crude material. (1.34 g, 38% purity, 69% assay yield). The resultant material was purified by silica gel chromatography (5-6% MeOH/DCM) to provide pure EIDD-2801 as two fractions (0.26 g, >99% purity, 36% corrected yield) as an yellow solid and 0.27 g (69.5% purity, 26% corrected yield) as a pinkish solid. The lower purity material was subjected to a second column purification again using 7% MeOH/ DCM to afford 0.137 g of material with 90% purity by NMR. The combined yield thus was estimated to be 53%. The 1H NMR spectrum of the product thus obtained matched the one obtained in the sequential approach as outlined above.

SYN

A High‐Yielding Synthesis of EIDD‐2801 from Uridine,
Alexander Steiner, Desiree Znidar, Sándor B. Ötvös, David R. Snead, Doris Dallinger, C. Oliver Kappe,
Eur. J. Org. Chem. 2020.
https://doi.org/10.1002/ejoc.202001340

A High‐Yielding Synthesis of EIDD‐2801 from Uridine** - Steiner - - European Journal of Organic Chemistry - Wiley Online Library

EIDD-2801 was isolated in 69% yield (307 mg) and ≥99% purity as a white
solid.
1H-NMR (300 MHz, MeOH-d4) δ 6.91 (d, J= 8.3 Hz, 1H), 5.82 (d, J= 4.8 Hz, 1H), 5.61 (d, J= 8.2 Hz, 1H), 4.29
(d, J= 3.6 Hz, 2H), 4.15-4.07 (m, 3H), 2.62 (sept, J= 7.0 Hz, 1H), 1.18 (d, J= 7.0 Hz 6H);

13C-NMR (75 MHz,
MeOH-d4Ϳ δ 178.2, 151.5, 146.1, 131.7, 99.5, 90.4, 82.5, 74.3, 71.5, 64.9, 35.1, 19.3, 19.3. The NMR data
is in agreement with previously published values.[2] HRMS (ESI, positive mode): m/z [M + H]+
Calcd for
[C13H20N3O7 +H]+
: 330.1296, found: 330.1297.

SYN

https://www.chemistryviews.org/details/ezine/11278339/High-Yielding_Synthesis_of_Antiviral_Drug_Candidate.html

C. Oliver Kappe, Doris Dallinger, University of Graz, Austria, and colleagues have developed an improved synthesis of EIDD-2801 from uridine (pictured below) by strategically reordering the synthetic steps. The reaction sequence starts with the activation of uridine with 1,2,4-triazole and continues with a telescoped acetonide protection/esterification and a telescoped hydroxyamination/acetonide deprotection. Telescoped reaction sequences consist of two or more than one one-pot procedures that are performed back-to-back without a work-up step in-between. A continuous flow process was used for the final acetonide deprotection, which improved selectivity and reproducibility.

SYN

https://www.frontiersin.org/articles/10.3389/fphar.2020.01013/full

Frontiers | Turning the Tide: Natural Products and Natural-Product-Inspired Chemicals as Potential Counters to SARS-CoV-2 Infection | Pharmacology

SYN

http://www.rsc.org/suppdata/d0/cc/d0cc05944g/d0cc05944g1.pdf

To a solution of 5’-O-isobutyrylcytidine 4 (1.0 g, 90% purity, 2.87 mmol, 1.0 eq) in 2-propanol (15 ml), hydroxylamine sulphate (2.12 g, 12.93 mmol, 4.5 eq.) was added and reaction was stirred for 20 h at 78 C. Upon completion, the reaction was cooled to room temperature. The organic layer (upper layer) was separated from biphasic reaction mixture. The aqueous layer was washed with 2-propanol (2 X 5 mL). The combined organic layer was concentrated using rotary evaporation and the crude was purified by column chromatography with a gradient of 2-15% methanol in dichloromethane to yield EIDD-2801 (1) as a white solid (963 mg, 94% purity, 96% yield). 1H NMR (600 MHz, D2O) δ 6.98 (d, J = 8.3 Hz, 1H), 5.87 (d, J = 5.0 Hz, 1H), 5.78 (d, J = 8.2 Hz, 1H), 4.39 – 4.33 (m, 3H), 4.28 (dd, J = 6.6, 3.4 Hz, 2H), 2.69 (hept, J = 7.0 Hz, 1H), 1.17 (d, J = 3.7 Hz, 3H), 1.16 (d, J = 3.7 Hz, 3H). 13C NMR (126 MHz, D2O) δ 18.1, 18.2, 33.9, 48.8, 63.6, 69.6, 72.5, 81.0, 88.5, 98.8, 131.1, 151.1, 179.8 ppm; LRMS: 330.1 [M+H]+ ; HRMS (ESI): calcd. for C13H19N3O7 [M+H]+ 330.1296, found 330.1302; Purity: 94% (assessed by qNMR).

https://pubs.rsc.org/en/content/articlehtml/2020/cc/d0cc05944g

A concise route to MK-4482 (EIDD-2801) from cytidine,Chemical Communications - X-MOL

A concise route to MK-4482 (EIDD-2801) from cytidine - Chemical Communications (RSC Publishing) DOI:10.1039/D0CC05944G


	Fig. 2 A new route to MK-4482 from cytidine.

References

^ Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. (October 2019). “Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia”. Science Translational Medicine. 11 (515): eaax5866. doi:10.1126/scitranslmed.aax5866. PMC 6848974. PMID 31645453.
^ Toots M, Yoon JJ, Hart M, Natchus MG, Painter GR, Plemper RK (April 2020). “Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model”. Translational Research. 218: 16–28. doi:10.1016/j.trsl.2019.12.002. PMID 31945316.
^ Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, et al. (April 2020). “An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice”. Science Translational Medicine. 12 (541): eabb5883. doi:10.1126/scitranslmed.abb5883. PMC 7164393. PMID 32253226.
^ Halford, Bethany. “An emerging antiviral takes aim at COVID-19”. Retrieved 1 August 2020.
^ Cohen, Jon; Piller, Charles (13 May 2020). “Emails offer look into whistleblower charges of cronyism behind potential COVID-19 drug”. Science. Retrieved 1 August 2020.
^ “COVID-19 First In Human Study to Evaluate Safety, Tolerability, and Pharmacokinetics of EIDD-2801 in Healthy Volunteers”. ClinicalTrials.gov. Retrieved 1 June 2020.
^ “Ridgeback Biotherapeutics Announces Launch of Phase 2 Trials Testing EIDD-2801 as Potential Treatment for COVID-19”. Business Wire. Retrieved 4 July 2020.
^ “A Safety, Tolerability and Efficacy of EIDD-2801 to Eliminate Infectious Virus Detection in Persons With COVID-19”. ClinicalTrials.gov. Retrieved 4 July 2020.
^ “The Effect of EIDD-2801 on Viral Shedding of SARS-CoV-2 (COVID-19)”. ClinicalTrials.gov. Retrieved 4 July 2020.
^ Court, Emma (31 July 2020). “Merck pushes ahead on COVID-19 treatment, vaccines”. Retrieved 31 July 2020.
^ ClinicaL trials register : Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001)

Story image

Electron microscope image of SARS virus in a tissue culture isolate, courtesy of CDC Public Health Image Library.

The drug EIDD-1931 was effective against SARS and MERS viruses in the laboratory, and a modified version (EIDD-2801) could potentially be valuable against 2019-nCoV.

https://news.emory.edu/stories/2020/02/coronavirus_eidd/index.html

Emory, collaborators testing antiviral drug as potential treatment for coronaviruses

An antiviral compound discovered at Emory University could potentially be used to treat the new coronavirus associated with the outbreak in China and spreading around the globe. Drug Innovation Ventures at Emory (DRIVE), a non-profit LLC wholly owned by Emory, is developing the compound, designated EIDD-2801.

In testing with collaborators at the University of North Carolina at Chapel Hill and Vanderbilt University Medical Center, the active form of EIDD-2801, which is called EIDD-1931, has shown efficacy against the related coronaviruses SARS (Severe Acute Respiratory Syndrome)- and MERS-CoV (Middle East Respiratory Syndrome Coronavirus). Some of the data was recently published in Journal of Virology.

EIDD-2801 is an oral ribonucleoside analog that inhibits the replication of multiple RNA viruses, including respiratory syncytial virus, influenza, chikungunya, Ebola, Venezuelan equine encephalitis virus, and Eastern equine encephalitis viruses.

“We have been planning to enter human clinical tests of EIDD-2801 for the treatment of influenza, and recognized that it has potential activity against the current novel coronavirus,” says George Painter, PhD, director of the Emory Institute for Drug Development (EIDD) and CEO of DRIVE. “Based on the drug’s broad-spectrum activity against viruses including influenza, Ebola and SARS-CoV/MERS-CoV, we believe it will be an excellent candidate.”

“Our studies in the Journal of Virology show potent activity of the EIDD-2801 parent compound against multiple coronaviruses including SARS and MERS,” says Mark Denison, MD, the Stahlman Professor of Pediatrics and director of pediatric infectious diseases at Vanderbilt University School of Medicine. “It also has a strong genetic barrier to development of viral resistance, and its oral bioavailability makes it a candidate for use during an outbreak.”

“Generally speaking, seasonal flu is still a much more common threat than this coronavirus, however, novel emerging coronaviruses represent a considerable threat to global health as evidenced by the new 2019-nCoV,” said Ralph Baric, PhD, an epidemiology professor at the University of North Carolina’s Gillings School of Global Public Health. “But the reason the new coronavirus is so concerning is that it’s much more likely to be deadly than the flu – fatal for about one in 25 people versus one in 1,000 for the flu.”

The development of EIDD-2801 has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), under contract numbers HHSN272201500008C and 75N93019C00058, and from the Defense Threat Reduction Agency (DTRA), under contract numbers HDTRA1-13-C-0072 and HDTRA1-15-C-0075, for the treatment of Influenza, coronavirus, chikungunya, and Venezuelan equine encephalitis virus.

About DRIVE: DRIVE is a non-profit LLC wholly owned by Emory started as an innovative approach to drug development. Operating like an early stage biotechnology company, DRIVE applies focus and industry development expertise to efficiently translate discoveries to address viruses of global concern. Learn more at: http://driveinnovations.org/

Emory-discovered antiviral is poised for COVID-19 clinical trials

The nucleoside inhibitor has advantages over Gilead’s remdesivir but has yet to be tested in humans

https://cen.acs.org/biological-chemistry/infectious-disease/Emory-discovered-antiviral-poised-COVID/98/i12?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN&fbclid=IwAR1yIuxNNrelRhKBdPp2hz3oRlqFrDtFYgTPEEORPf1G2R30RIhPIYD9Iwg

Asmall-molecule antiviral discovered by Emory University chemists could soon start human testing against COVID-19, the respiratory disease caused by the novel coronavirus. That’s the plan of Ridgeback Biotherapeutics, which licensed the compound, EIDD-2801, from an Emory nonprofit.

EIDD-2801 works similarly to Gilead Sciences’ remdesivir, an unapproved drug that was developed for the Ebola virus and is being studied in five Phase III trials against COVID-19. Both molecules are nucleoside analogs that metabolize into an active form that blocks RNA polymerase, an essential component of viral replication.

But remdesivir can only be given intravenously, meaning it would be difficult to deploy widely. In contrast, EIDD-2801 can be taken in pill form, says Mark Denison, a coronavirus expert and director of the infectious diseases division at Vanderbilt Medical School. Denison partnered with Emory and researchers at the University of North Carolina to test the compound against coronaviruses.

EIDD-2801 has other promising features. Many antivirals work by introducing errors into the viral genome, but, unlike other viruses, coronaviruses can fix some mistakes. In lab experiments, EIDD-2801 “was able to overcome the coronavirus proofreading function,” Denison says.

He also notes that while remdesivir and EIDD-2801 both block RNA polymerase, they appear to do it in different ways, meaning they could be complementary.

Unlike remdesivir, EIDD-2801 lacks human safety data. Ridgeback founder and CEO Wendy Holman says she expects the US Food and Drug Administration to give the green light for a Phase I study in COVID-19 infections within “weeks, not months.”

“weeks, not months.”

Molnupiravir
Clinical data

Other names	MK-4482, EIDD-2801
Legal status
Legal status	US: Investigational drug
Identifiers
IUPAC name [show]
CAS Number	2349386-89-4
PubChem CID	145996610
UNII	YA84KI1VEW
Chemical and physical data
Formula	C₁₃H₁₉N₃O₇
Molar mass	329.31 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CC(C)C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=CC(=NC2=O)NO)O)O
InChI [hide] InChI=1S/C13H19N3O7/c1-6(2)12(19)22-5-7-9(17)10(18)11(23-7)16-4-3-8(15-21)14-13(16)20/h3-4,6-7,9-11,17-18,21H,5H2,1-2H3,(H,14,15,20)/t7-,9-,10-,11-/m1/s1 Key:HTNPEHXGEKVIHG-QCNRFFRDSA-N

////////EIDD 2801, EMORY, CORONA VIRUS, COVID 19, mk 4482, molnupiravir, merck

CC(C)C(=O)OC[C@H]2O[C@@H](N1C=CC(=NC1=O)NO)[C@H](O)[C@@H]2O

NEW DRUG APPROVALS

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Application Id	Application Number	Application Date	Country	Title
US333828014	17170172	08.02.2021	US	N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
US305251595	16755779	07.12.2018	US	N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
WO2021159044	PCT/US2021/016984	07.02.2021	WO	N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO
WO2021137913	PCT/US2020/054857	08.10.2020	WO	4′-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO

CHLOROQUINE, クロロキン;Хлорохин , クロロキン , كلوروكين

March 25, 2020 8:44 am / 1 Comment on CHLOROQUINE, クロロキン;Хлорохин , クロロキン , كلوروكين

Chloroquine

CHLOROQUINE

N4-(7-Chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine

Хлорохин [Russian] [INN]

クロロキン [Japanese]

كلوروكين [Arabic] [INN]

Formula	C18H26ClN3
CAS	54-05-7
Mol weight	319.8721

CAS Registry Number: 54-05-7

CAS Name: N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine

Additional Names: 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline

Manufacturers’ Codes: SN-7618; RP-3377

Molecular Formula: C18H26ClN3

Molecular Weight: 319.87

Percent Composition: C 67.59%, H 8.19%, Cl 11.08%, N 13.14%

Literature References: Prepd by the condensation of 4,7-dichloroquinoline with 1-diethylamino-4-aminopentane: DE 683692 (1939); H. Andersag et al., US 2233970 (1941 to Winthrop); Surrey, Hammer, J. Am. Chem. Soc. 68, 113 (1946). Review: Hahn in Antibiotics vol. 3, J. W. Corcoran, F. E. Hahn, Eds. (Springer-Verlag, New York, 1975) pp 58-78. Comprehensive description: D. D. Hong, Anal. Profiles Drug Subs. 5, 61-85 (1976). Comparative clinical trial with dapsone in rheumatoid arthritis: P. D. Fowler et al., Ann. Rheum. Dis. 43, 200 (1984); with penicillamine: T. Gibson et al., Br. J. Rheumatol. 26, 279 (1987).

Properties: mp 87°.

Melting point: mp 87°

Derivative Type: Diphosphate

CAS Registry Number: 50-63-5

Trademarks: Arechin (Polfa); Avloclor (AstraZeneca); Malaquin (Ahn Gook); Resochin (Bayer)

Molecular Formula: C18H26ClN3.2H3PO4

Molecular Weight: 515.86

Percent Composition: C 41.91%, H 6.25%, Cl 6.87%, N 8.15%, P 12.01%, O 24.81%

Properties: Bitter, colorless crystals. Dimorphic. One modification, mp 193-195°; the other, mp 215-218°. Freely sol in water; pH of 1% soln about 4.5; less sol at neutral and alkaline pH. Stable to heat in solns of pH 4.0 to 6.5. Practically insol in alcohol, benzene, chloroform, ether.

Melting point: mp 193-195°; mp 215-218°

Derivative Type: Sulfate

CAS Registry Number: 132-73-0

Trademarks: Aralen (Sanofi-Synthelabo); Nivaquine (Aventis)

Molecular Formula: C18H26ClN3.H2SO4

Molecular Weight: 417.95

Percent Composition: C 51.73%, H 6.75%, Cl 8.48%, N 10.05%, S 7.67%, O 15.31%

Therap-Cat: Antimalarial; antiamebic; antirheumatic. Lupus erythematosus suppressant.

Keywords: Antiamebic; Antiarthritic/Antirheumatic; Antimalarial; Lupus Erythematosus Suppressant.

Chloroquine is a medication used primarily to prevent and to treat malaria in areas where that parasitic disease is known to remain sensitive to its effects.^[1] A benefit of its use in therapy, when situations allow, is that it can be taken by mouth (versus by injection).^[1] Controlled studies of cases involving human pregnancy are lacking, but the drug may be safe for use for such patients.^{[verification needed]}^[1]^[2] However, the agent is not without the possibility of serious side effects at standard doses,^[1]^[3] and complicated cases, including infections of certain types or caused by resistant strains, typically require different or additional medication.^[1] Chloroquine is also used as a medication for rheumatoid arthritis, lupus erythematosus, and other parasitic infections (e.g., amebiasis occurring outside of the intestines).^[1] Beginning in 2020, studies have proceeded on its use as a coronavirus antiviral, in possible treatment of COVID-19.^[4]

Chloroquine, otherwise known as chloroquine phosphate, is in the 4-aminoquinoline class of drugs.^[1] As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell.^[1] In its use against rheumatoid arthritis and lupus erythematosus, its activity as a mild immunosuppressive underlies its mechanism.^[1] Antiviral activities, established and putative, are attributed to chloroquines inhibition of glycosylation pathways (of host receptor sialylation or virus protein post-translational modification), or to inhibition of virus endocytosis (e.g., via alkalisation of endosomes), or other possible mechanisms.^[5] Common side effects resulting from these therapeutic uses, at common doses, include muscle problems,^{[clarification needed]} loss of appetite, diarrhea, and skin rash.^{[clarification needed]}^[1] Serious side effects include problems with vision (retinopathy), muscle damage, seizures, and certain anemias.^[1]^[6]

Chloroquine was discovered in 1934 by Hans Andersag.^[7]^[8] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[9] It is available as a generic medication.^[1] The wholesale cost in the developing world is about US$0.04.^[10] In the United States, it costs about US$5.30 per dose.^[1]

Medical uses

Malaria

Distribution of malaria in the world:^[11]
♦ Elevated occurrence of chloroquine- or multi-resistant malaria
♦ Occurrence of chloroquine-resistant malaria
♦ No Plasmodium falciparum or chloroquine-resistance
♦ No malaria

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.^[12]^[13]

Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it.^[14] In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.^[15]

Amebiasis

In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.^[16]

Rheumatic disease

As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus.^[1]

Side effects

Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.^[17]^[18]

Unwanted/uncontrolled movements (including tongue and face twitching) ^[17]
Deafness or tinnitus.^[17]
Nausea, vomiting, diarrhea, abdominal cramps^[18]
Headache.^[17]
Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)^[17]^[18]
Signs of serious infection (such as high fever, severe chills, persistent sore throat)^[17]
Skin itchiness, skin color changes, hair loss, and skin rashes.^[18]^[19]
- Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.^[20]
Unpleasant metallic taste
- This could be avoided by “taste-masked and controlled release” formulations such as multiple emulsions.^[21]
Chloroquine retinopathy
Electrocardiographic changes^[22]
- This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.^[23]

Pregnancy

Chloroquine has not been shown to have any harmful effects on the fetus when used for malarial prophylaxis.^[24] Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body.^[23]^[25] Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.^[24]

Elderly

There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.^[23]

Drug interactions

Chloroquine has a number of drug-drug interactions that might be of clinical concern:^{[citation needed]}

Ampicillin– levels may be reduced by chloroquine;^[23]
Antacids– may reduce absorption of chloroquine;^[23]
Cimetidine– may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;^[23]
Cyclosporine– levels may be increased by chloroquine;^[23] and
Mefloquine– may increase risk of convulsions.^[23]

Overdose

Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut. In 1961, a published compilation of case reports contained accounts of three children who took overdoses and died within 2.5 hours of taking the drug. While the amount of the overdose was not stated, the therapeutic index for chloroquine is known to be small.^[26] One of the children died after taking 0.75 or 1 gram, or twice a single therapeutic amount for children. Symptoms of overdose include headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, seizures, and sudden respiratory and cardiac arrest.^[23]

An analog of chloroquine – hydroxychloroquine – has a long half-life (32–56 days) in blood and a large volume of distribution (580–815 L/kg).^[27] The therapeutic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/l, 3.0 to 26 mg/l and 20 to 104 mg/l, respectively. However, nontoxic cases have been reported up to 39 mg/l, suggesting individual tolerance to this agent may be more variable than previously recognised.^[27]

Pharmacology

Chloroquine’s absorption of the drug is rapid. It is widely distributed in body tissues. It’s protein binding is 55%.^[ It’s metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. It’s excretion os ≥50% as unchanged drug in urine, where acidification of urine increases its elimination It has a very high volume of distribution, as it diffuses into the body’s adipose tissue.

Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pK_a for the quinoline nitrogen of chloroquine is 8.5, meaning—in simplified terms, considering only this basic site—it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation) This decreases to about 0.2% at a lysosomal pH of 4.6.Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative “trapping” of the compound in lysosomes results.

Mechanism of action

Medical quinolines

Malaria

Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth.

The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases,^[28]^[29] autophagy, and apoptosis.^[30]

Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.^{[citation needed]}

Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.^{[citation needed]}

Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. ^[31] Parasites that do not form hemozoin are therefore resistant to chloroquine.^[32]

Resistance in malaria[edit source]

Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog’s eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole.^[33] Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca²⁺ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved.^[34] Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.^{[citation needed]}

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.^[35]

Antiviral

Chloroquine has antiviral effects.^[36] It increases late endosomal or lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.^[37]^[38]

Chloroquine also seems to act as a zinc ionophore, that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.^[39]^[40]

Other

Chloroquine inhibits thiamine uptake.^[41] It acts specifically on the transporter SLC19A3.

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

History

In Peru the indigenous people extracted the bark of the Cinchona plant^[42] trees and used the extract (Chinchona officinalis) to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria.^[43] The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.

Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it “Resochin”.^[44] It was ignored for a decade, because it was considered too toxic for human use. During World War II, United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.^[45]

Society and culture

Resochin tablet package

Formulations

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.^[46]

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.^[47]

Other animals

Chloroquine is used to control the aquarium fish parasite Amyloodinium ocellatum.^[48]

Research

COVID-19

In late January 2020 during the 2019–20 coronavirus outbreak, Chinese medical researchers stated that exploratory research into chloroquine and two other medications, remdesivir and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on the SARS-CoV-2 virus, which is the virus that causes COVID-19. Requests to start clinical testing were submitted.^[49] Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.^[50]^[51]

Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19.^[52]^[53] These agencies noted contraindications for people with heart disease or diabetes.^[54] Both chloroquine and hydroxychloroquine were shown to inhibit SARS-CoV-2 in vitro, but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile.^[55] Preliminary results from a trial suggested that chloroquine is effective and safe in COVID-19 pneumonia, “improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.”^[56] Self-medication with chloroquine has caused one known fatality.^[57]

On 24 March 2020, NBC News reported^[58] a fatality due to misuse of a chloroquine product used to control fish parasites.^[59]

Other viruses

In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.^[60]

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.^[61]

Other

The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.^[62]^[63] In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.

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^ Martin RE, Marchetti RV, Cowan AI, Howitt SM, Bröer S, Kirk K (September 2009). “Chloroquine transport via the malaria parasite’s chloroquine resistance transporter”. Science. 325 (5948): 1680–2. Bibcode:2009Sci…325.1680M. doi:10.1126/science.1175667. PMID 19779197.
^ Essentials of medical pharmacology fifth edition 2003, reprint 2004, published by-Jaypee Brothers Medical Publisher Ltd, 2003, KD Tripathi, pages 739,740.
^ Alcantara LM, Kim J, Moraes CB, Franco CH, Franzoi KD, Lee S, et al. (June 2013). “Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites”. Experimental Parasitology. 134 (2): 235–43. doi:10.1016/j.exppara.2013.03.022. PMID 23541983.
^ Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 2003). “Effects of chloroquine on viral infections: an old drug against today’s diseases?”. The Lancet. Infectious Diseases. 3(11): 722–7. doi:10.1016/s1473-3099(03)00806-5. PMID 14592603.
^ Al-Bari MA (February 2017). “Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases”. Pharmacology Research & Perspectives. 5 (1): e00293. doi:10.1002/prp2.293. PMC 5461643. PMID 28596841.
^ Fredericksen BL, Wei BL, Yao J, Luo T, Garcia JV (November 2002). “Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus”. Journal of Virology. 76 (22): 11440–6. doi:10.1128/JVI.76.22.11440-11446.2002. PMC 136743. PMID 12388705.
^ Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ (1 October 2014). “Chloroquine is a zinc ionophore”. PloS One. 9(10): e109180. doi:10.1371/journal.pone.0109180. PMC 4182877. PMID 25271834.
^ te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ (November 2010). “Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture”. PLoS Pathogens. 6 (11): e1001176. doi:10.1371/journal.ppat.1001176. PMC 2973827. PMID 21079686.
^ Huang Z, Srinivasan S, Zhang J, Chen K, Li Y, Li W, et al. (2012). “Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy”. PLOS Genetics. 8 (11): e1003083. doi:10.1371/journal.pgen.1003083. PMC 3510038. PMID 23209439.
^ Fern, Ken (2010–2020). “Cinchona officinalis – L.” Plans for a Future. Archived from the original on 25 August 2017. Retrieved 2 February 2020.
^ V. Kouznetsov, Vladímir (2008). “Antimalarials: construction of molecular hybrids based on chloroquine” (PDF). Universitas Scientiarum: 1. Archived (PDF) from the original on 22 February 2020. Retrieved 22 February 2020 – via scielo.
^ Krafts K, Hempelmann E, Skórska-Stania A (July 2012). “From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy”. Parasitology Research. 111 (1): 1–6. doi:10.1007/s00436-012-2886-x. PMID 22411634.
^ “The History of Malaria, an Ancient Disease”. Centers for Disease Control. 29 July 2019. Archived from the original on 28 August 2010.
^ “Chloroquine”. nih.gov. National Institutes of Health. Retrieved 24 March 2020.
^ “Ipca Laboratories: Formulations – Branded”. Archived from the original on 6 April 2019. Retrieved 14 March 2020.
^ Francis-Floyd, Ruth; Floyd, Maxine R. “Amyloodinium ocellatum, an Important Parasite of Cultured Marine Fish” (PDF). agrilife.org.
^ “Could an old malaria drug help fight the new coronavirus?”. asbmb.org. Archived from the original on 6 February 2020. Retrieved 6 February 2020.
^ Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (October 2004). “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine”. Biochemical and Biophysical Research Communications. 323 (1): 264–8. doi:10.1016/j.bbrc.2004.08.085. PMID 15351731.
^ Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 Mar 11:105938. doi:10.1016/j.ijantimicag.2020.105938 PMID 32171740
^ “Physicians work out treatment guidelines for coronavirus”. m.koreabiomed.com (in Korean). 13 February 2020. Archivedfrom the original on 17 March 2020. Retrieved 18 March 2020.
^ “Azioni intraprese per favorire la ricerca e l’accesso ai nuovi farmaci per il trattamento del COVID-19”. aifa.gov.it (in Italian). Retrieved 18 March 2020.
^ “Plaquenil (hydroxychloroquine sulfate) dose, indications, adverse effects, interactions… from PDR.net”. http://www.pdr.net. Archivedfrom the original on 18 March 2020. Retrieved 19 March 2020.
^ Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. (March 2020). “In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”. Clinical Infectious Diseases. doi:10.1093/cid/ciaa237. PMID 32150618.
^ Gao J, Tian Z, Yang X (February 2020). “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies”. Bioscience Trends. 14: 72–73. doi:10.5582/bst.2020.01047. PMID 32074550. Archived from the original on 19 March 2020. Retrieved 19 March 2020.
^ Edwards, Erika; Hillyard, Vaughn (23 March 2020). “Man dies after ingesting chloroquine in an attempt to prevent coronavirus”. NBC News. Retrieved 24 March 2020.
^ “A man died after ingesting a substance he thought would protect him from coronavirus”. NBC News. Retrieved 25 March 2020.
^ “Banner Health experts warn against self-medicating to prevent or treat COVID-19”. Banner Health (Press release). 23 March 2020. Retrieved 25 March 2020.
^ Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (October 2004). “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine”. Biochemical and Biophysical Research Communications. 323 (1): 264–8. doi:10.1016/j.bbrc.2004.08.085. PMID 15351731.
^ Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 2003). “Effects of chloroquine on viral infections: an old drug against today’s diseases?”. The Lancet. Infectious Diseases. 3(11): 722–7. doi:10.1016/S1473-3099(03)00806-5. PMID 14592603.
^ Savarino A, Lucia MB, Giordano F, Cauda R (October 2006). “Risks and benefits of chloroquine use in anticancer strategies”. The Lancet. Oncology. 7 (10): 792–3. doi:10.1016/S1470-2045(06)70875-0. PMID 17012039.
^ Sotelo J, Briceño E, López-González MA (March 2006). “Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial”. Annals of Internal Medicine. 144 (5): 337–43. doi:10.7326/0003-4819-144-5-200603070-00008. PMID 16520474.
“Summaries for patients. Adding chloroquine to conventional chemotherapy and radiotherapy for glioblastoma multiforme”. Annals of Internal Medicine. 144 (5): I31. March 2006. doi:10.7326/0003-4819-144-5-200603070-00004. PMID 16520470.

External links

“Chloroquine”. Drug Information Portal. U.S. National Library of Medicine.

“Medicines for the Prevention of Malaria While Traveling – Chloroquine (Aralen)” (PDF) (Fact sheet). U.S. Centers for Disease Control and Prevention (CDC).
The dictionary definition of chloroquine at Wiktionary

Chloroquine
Clinical data


Pronunciation	/ˈklɔːrəkwɪn/
Trade names	Aralen, other
Other names	Chloroquine phosphate
AHFS/Drugs.com	Monograph
License data	US DailyMed: Chloroquine US FDA: Chloroquine
ATC code	P01BA01 (WHO)
Legal status
Legal status	UK: P (Pharmacy medicines) US: ℞-only
Pharmacokinetic data
Metabolism	Liver
Elimination half-life	1-2 months
Identifiers
IUPAC name [show]
CAS Number	54-05-7
PubChem CID	2719
IUPHAR/BPS	5535
DrugBank	DB00608
ChemSpider	2618
UNII	886U3H6UFF
KEGG	D02366
ChEBI	CHEBI:3638
ChEMBL	ChEMBL76
NIAID ChemDB	000733
CompTox Dashboard (EPA)	DTXSID2040446
ECHA InfoCard	100.000.175
Chemical and physical data
Formula	C₁₈H₂₆ClN₃
Molar mass	319.872 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] Clc1cc2nccc(c2cc1)NC(C)CCCN(CC)CC

//////////////CHLOROQUINE,, クロロキン, ANTIMALARIAL, COVID 19, CORONA VIRUS, Хлорохин , クロロキン , كلوروكين

Niclosamide, ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 ,

March 24, 2020 4:02 am / Leave a comment

Niclosamide

ChemSpider 2D Image | Niclosamide | C13H8Cl2N2O4

Niclosamide

ニクロサミド;

Formula	C13H8Cl2N2O4
cas	50-65-7
Mol weight	327.1196

никлосамид [Russian] [INN]

نيكلوساميد [Arabic] [INN]

氯硝柳胺 [Chinese] [INN]

Niclosamide [BSI] [INN] [ISO] [USAN] [Wiki]

1532

2′,5-Dichlor-4′-nitro-salizylsaeureanilid [German]

2′,5-Dichloro-4′-nitrosalicylanilide

200-056-8 [EINECS]

2820605

50-65-7 [RN]

]

5-Chlor-N-(2-chlor-4-nitrophenyl)-2-hydroxybenzolcarboxamid

5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide

CAS Registry Number: 50-65-7

CAS Name: 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide

Additional Names: 2¢,5-dichloro-4¢-nitrosalicylanilide; 5-chloro-N-(2¢-chloro-4¢-nitrophenyl)salicylamide; 5-chlorosalicyloyl-(o-chloro-p-nitranilide); N-(2¢-chloro-4¢-nitrophenyl)-5-chlorosalicylamide

Manufacturers’ Codes: Bayer 2353

Trademarks: Cestocide (Bayer); Niclocide (Miles); Ruby (Spencer); Trédémine (RPR); Yomesan (Bayer)

Molecular Formula: C13H8Cl2N2O4

Molecular Weight: 327.12

Percent Composition: C 47.73%, H 2.47%, Cl 21.68%, N 8.56%, O 19.56%

Literature References: Prepn: GB 824345 (1959 to Bayer), C.A. 54, 15822b (1960). See also: E. Schraufstätter, R. Gönnert, US 3079297; R. Strufe et al., US 3113067 (both 1963 to Bayer); Bekhli et al., Med. Prom. SSSR 1965, 25.

Properties: Pale yellow crystals, mp 225-230°. Practically insol in water. Sparingly sol in ethanol, chloroform, ether.

Melting point: mp 225-230°

Derivative Type: Ethanolamine salt

CAS Registry Number: 1420-04-8

Additional Names: Clonitrilide

Trademarks: Bayluscid (Bayer)

Molecular Formula: C13H8Cl2N2O4.C2H7NO

Molecular Weight: 388.20

Percent Composition: C 46.41%, H 3.89%, Cl 18.27%, N 10.82%, O 20.61%

Properties: Yellow-brown solid, mp 204°.

Melting point: mp 204°

Use: The ethanolamine salt as a molluscicide.

Therap-Cat: Anthelmintic (Cestodes).

Therap-Cat-Vet: Anthelmintic (Cestodes).

Keywords: Anthelmintic (Cestodes).

Niclosamide, sold under the brand name Niclocide among others, is a medication used to treat tapeworm infestations.^[2] This includes diphyllobothriasis, hymenolepiasis, and taeniasis.^[2] It is not effective against other worms such as pinworms or roundworms.^[3] It is taken by mouth.^[2]

Side effects include nausea, vomiting, abdominal pain, and itchiness.^[2] It may be used during pregnancy and appears to be safe for the baby.^[2] Niclosamide is in the anthelmintic family of medications.^[3] It works by blocking the uptake of sugar by the worm.^[4]

Niclosamide was discovered in 1958.^[5] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[6] The wholesale cost in the developing world is about 0.24 USD for a course of treatment.^[7] It is not commercially available in the United States.^[3] It is effective in a number of other animals.^[4]

Side effects

Side effects include nausea, vomiting, abdominal pain, constipation, and itchiness.^[2] Rarely, dizziness, skin rash, drowsiness, perianal itching, or an unpleasant taste occur. For some of these reasons, praziquantel is a preferable and equally effective treatment for tapeworm infestation.^{[citation needed]}

Mechanism of action

Niclosamide inhibits glucose uptake, oxidative phosphorylation, and anaerobic metabolism in the tapeworm.^[8]

Other applications

Niclosamide’s metabolic effects are relevant to wide ranges of organisms, and accordingly it has been applied as a control measure to organisms other than tapeworms. For example, it is an active ingredient in some formulations such as Bayluscide for killing lamprey larvae,^[9]^[10] as a molluscide,^[11] and as a general purpose piscicide in aquaculture. Niclosamide has a short half-life in water in field conditions; this makes it valuable in ridding commercial fish ponds of unwanted fish; it loses its activity soon enough to permit re-stocking within a few days of eradicating the previous population.^[11] Researchers have found that niclosamide is effective in killing invasive zebra mussels in cool waters.^[12]

Research

Niclosamide is being studied in a number of types of cancer.^[13] Niclosamide along with oxyclozanide, another anti-tapeworm drug, was found in a 2015 study to display “strong in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA)”.^[14]

syn

https://www.sciencedirect.com/science/article/pii/S0099542805320028

Image result for niclosamide

References

^ Jump up to:^a ^b ^c ^d ^e ^f World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 81, 87, 591. hdl:10665/44053. ISBN 9789241547659.
^ Jump up to:^a ^b ^c “Niclosamide Advanced Patient Information – Drugs.com”. http://www.drugs.com. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
^ Jump up to:^a ^b Jim E. Riviere; Mark G. Papich (13 May 2013). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. p. 1096. ISBN 978-1-118-68590-7. Archived from the original on 10 September 2017.
^ Mehlhorn, Heinz (2008). Encyclopedia of Parasitology: A-M. Springer Science & Business Media. p. 483. ISBN 9783540489948. Archived from the original on 2016-12-20.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ “Niclosamide”. International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 1 December 2016.
^ Weinbach EC, Garbus J (1969). “Mechanism of action of reagents that uncouple oxidative phosphorylation”. Nature. 221 (5185): 1016–8. doi:10.1038/2211016a0. PMID 4180173.
^ Boogaard, Michael A. Delivery Systems of Piscicides “Request Rejected”(PDF). Archived (PDF) from the original on 2017-06-01. Retrieved 2017-05-30.
^ Verdel K.Dawson (2003). “Environmental Fate and Effects of the Lampricide Bayluscide: a Review”. Journal of Great Lakes Research. 29 (Supplement 1): 475–492. doi:10.1016/S0380-1330(03)70509-7.
^ Jump up to:^a ^b “WHO Specifications And Evaluations. For Public Health Pesticides. Niclosamide” (PDF).^{[dead link]}
^ “Researchers find new methods to combat invasive zebra mussels”. The Minnesota Daily. Retrieved 2018-11-19.
^ “Clinical Trials Using Niclosamide”. NCI. Retrieved 20 March 2019.
^ Rajamuthiah R, Fuchs BB, Conery AL, Kim W, Jayamani E, Kwon B, Ausubel FM, Mylonakis E (April 2015). Planet PJ (ed.). “Repurposing Salicylanilide Anthelmintic Drugs to Combat Drug Resistant Staphylococcus aureus”. PLoS ONE. 10 (4): e0124595. doi:10.1371/journal.pone.0124595. ISSN 1932-6203. PMC 4405337. PMID 25897961.

External links

“Niclosamide”. Drug Information Portal. U.S. National Library of Medicine.
Taber, Clarence Wilbur; Venes, Donald; Thomas, Clayton L. (2001). Taber’s cyclopedic medical dictionary. Philadelphia: F.A.Davis Co.
Niclosamide in the Pesticide Properties DataBase (PPDB)
“MedlinePlus Drug Information: Niclosamide (Oral)”. MedlinePlus. U.S. National Library of Medicine. 1995-06-23. Archived from the original on 2006-12-16.
World Health Organization (1995). “Helminths: Cestode (tapeworm) infection: Niclosamide”. WHO model prescribing information : drugs used in parasitic diseases (2nd ed.). World Health Organization (WHO). hdl:10665/41765.

Niclosamide

Niclosamide
Clinical data

Trade names	Niclocide, Fenasal, Phenasal, others^[1]
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	By mouth
ATC code	P02DA01 (WHO) QP52AG03 (WHO)
Identifiers
IUPAC name [show]
CAS Number	50-65-7
PubChem CID	4477
DrugBank	DB06803
ChemSpider	4322
UNII	8KK8CQ2K8G
KEGG	D00436
ChEBI	CHEBI:7553
ChEMBL	ChEMBL1448
CompTox Dashboard (EPA)	DTXSID7040362
ECHA InfoCard	100.000.052
Chemical and physical data
Formula	C₁₃H₈Cl₂N₂O₄
Molar mass	327.119 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
Melting point	225 to 230 °C (437 to 446 °F)
SMILES [hide] Clc2cc(ccc2NC(=O)c1cc(Cl)ccc1O)[N+]([O-])=O

//////////Niclosamide ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 , covid 19, corona virus

Nitazoxanide ニタゾキサニド;

March 22, 2020 11:36 am / Leave a comment

Nitazoxanide

Formula	C12H9N3O5S
Exact mass	307.0263
Mol weight	307.282

Nitazoxanide

CAS Registry Number: 55981-09-4

CAS Name: 2-(Acetyloxy)-N-(5-nitro-2-thiazolyl)benzamide

Additional Names: N-(5-nitro-2-thiazolyl)salicylamide acetate (ester); 2-(2¢-acetoxy)benzamido-5-nitrothiazole

Manufacturers’ Codes: PH-5776

Trademarks: Alinia (Romark); Cryptaz (Romark)

Molecular Formula: C12H9N3O5S

Molecular Weight: 307.28

Percent Composition: C 46.90%, H 2.95%, N 13.67%, O 26.03%, S 10.44%

Literature References: Broad spectrum antiparasitic agent; inhibits pyruvate ferredoxin oxidoreductase. Prepn: J. F. Rossignol, R. Cavier, DE 2438037; eidem, US 3950351 (1975, 1976 both to S.P.R.L. Phavic); and antiparasitic activity: R. Cavier et al., Eur. J. Med. Chem. – Chim. Ther. 13, 539 (1978). Antibacterial spectrum in vitro: L Dubreuil et al., Antimicrob. Agents Chemother. 40, 2266 (1996). Toxicology: J. R. Murphy, J.-C. Friedmann, J. Appl. Toxicol. 5, 49 (1985). Clinical pharmacokinetics: A. Stockis et al., Int. J. Clin. Pharmacol. Ther. 34, 349 (1996). Clinical trial in intestinal protozoan and helminthic infections: H. Abaza et al., Curr. Ther. Res. 59, 116 (1998). Review of mechanism of action and clinical experience: H. M. Gilles, P. S. Hoffman, Trends Parasitol. 18, 95-97 (2002).

Properties: Light yellow crystalline powder. Crystals from methanol, mp 202°. Poorly sol in ethanol. Practically insol in water. LD50 orally in male, female mice: 1350, 1380 mg/kg; in rats: >10 g/kg (Murphy, Friedmann).

Melting point: mp 202°

Toxicity data: LD50 orally in male, female mice: 1350, 1380 mg/kg; in rats: >10 g/kg (Murphy, Friedmann)

Therap-Cat: Anthelmintic (cestodes); antiprotozoal (Cryptosporidium).

Keywords: Anthelmintic (Cestodes); Antiprotozoal (Cryptosporidium).

Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum antiviral drug that is used in medicine for the treatment of various helminthic, protozoal, and viral infections.^[4]^[5]^[6] It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza.^[1]^[6] Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths;^[4]^[7] emerging evidence suggests that it possesses efficacy in treating a number of viral infections as well.^[6]

Chemically, nitazoxanide is the prototype member of the thiazolides, a class of drugs which are synthetic nitrothiazolyl-salicylamide derivatives with antiparasitic and antiviral activity.^[4]^[6]^[8] Tizoxanide, an active metabolite of nitazoxanide in humans, is also an antiparasitic drug of the thiazolide class.^[4]^[9]

Uses

Nitazoxanide is an effective first-line treatment for infection by Blastocystis species^[10]^[11] and is indicated for the treatment of infection by Cryptosporidium parvum or Giardia lamblia in immunocompetent adults and children.^[1] It is also an effective treatment option for infections caused by other protozoa and helminths (e.g., Entamoeba histolytica,^[12] Hymenolepis nana,^[13] Ascaris lumbricoides,^[14] and Cyclospora cayetanensis^[15]).^[7]

As of September 2015, it is in phase 3 clinical trials for the treatment influenza due to its inhibitory effect on a broad range of influenza virus subtypes and efficacy against influenza viruses that are resistant to neuraminidase inhibitors like oseltamivir.^[6]^[16] Nitazoxanide is also being researched as a potential treatment for chronic hepatitis B, chronic hepatitis C, rotavirus and norovirus gastroenteritis.^[6]

Chronic hepatitis B

Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one-year course of therapy.^[17] Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg. Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg.^[18] These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase Ⅱ study is being planned for 2009.^[19]

Chronic hepatitis C

Romark initially decided to focus on the possibility of treating chronic hepatitis C with nitazoxanide.^[20] The drug garnered interest from the hepatology community after three phase II clinical trials involving the treatment of hepatitis C with nitazoxanide produced positive results for treatment efficacy and similar tolerability to placebo without any signs of toxicity.^[20] A meta-analysis from 2014 concluded that the previous held trials were of low-quality and with held with a risk of bias. The authors concluded that more randomized trials with low risk of bias are needed to give any determine if Nitazoxanide can be used as an effective treatment for chronic hepatitis C patients.^[21]

Clinical trials

Nitazoxanide has gone through Phase II clinical trials for the treatment of hepatitis C, in combination with peginterferon alfa-2a and ribavirin.^[22]^[23]Romark Laboratories has announced encouraging results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus infection. The company used 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events. Primarily GI-related adverse events were reported.

A randomised double-blind placebo-controlled study published in 2006, with a group of 38 young children (Lancet, vol 368, page 124-129)^[24] concluded that a 3-day course of nitazoxanide significantly reduced the duration of rotavirus disease in hospitalized pediatric patients. Dose given was “7.5 mg/kg twice daily” and the time of resolution was “31 hours for those given nitazoxanide compared with 75 hours for those in the placebo group.” Rotavirus is the most common infectious agent associated with diarrhea in the pediatric age group worldwide.

Teran et al.. conducted a study at the Pediatric Center Albina Patinö, a reference hospital in the city of Cochabamba, Bolivia, from August 2007 to February 2008. The study compared nitazoxanide and probiotics in the treatment of acute rotavirus diarrhea. They found Small differences in favor of nitazoxanide in comparison with probiotics and concluded that nitazoxanide is an important treatment option for rotavirus diarrhea.^[17]

Lateef et al.. conducted a study in India that evaluated the effectiveness of nitazoxanide in the treatment of beef tapeworm (Taenia saginata) infection. They concluded that nitazoxanide is a safe, effective, inexpensive, and well-tolerated drug for the treatment of niclosamide- and praziquantel-resistant beef tapeworm (Taenia saginata) infection.^[18]

A retrospective review of charts of patients treated with nitazoxanide for trichomoniasis by Michael Dan and Jack D. Sobel demonstrated negative result. They reported three case studies; two of which with metronidazole-resistant infections. In Case 3, they reported the patient to be cured with high divided dose tinidazole therapy. They used a high dosage of the drug (total dose, 14–56 g) than the recommended standard dosage (total dose, 3 g) and observed a significant adverse reaction (poorly tolerated nausea) only with the very high dose (total dose, 56 g). While confirming the safety of the drug, they showed nitazoxanide is ineffective for the treatment of trichomoniasis.^[25]

Contraindications

Nitazoxanide is contraindicated only in individuals who have experienced a hypersensitivity reaction to nitazoxanide or the inactive ingredients of a nitazoxanide formulation.^[1]

Adverse effects

The side effects of nitazoxanide do not significantly differ from a placebo treatment for giardiasis;^[1] these symptoms include stomach pain, headache, upset stomach, vomiting, discolored urine, excessive urinating, skin rash, itching, fever, flu syndrome, and others.^[1]^[26] Nitazoxanide does not appear to cause any significant adverse effects when taken by healthy adults.^[1]^[2]

Overdose

Information on nitazoxanide overdose is limited. Oral doses of 4 grams in healthy adults do not appear to cause any significant adverse effects.^[1]^[2] In various animals, the oral LD₅₀ is higher than 10 g/kg.^[1]

Interactions

Due to the exceptionally high plasma protein binding (>99.9%) of nitazoxanide’s metabolite, tizoxanide, the concurrent use of nitazoxanide with other highly plasma protein-bound drugs with narrow therapeutic indices (e.g., warfarin) increases the risk of drug toxicity.^[1] In vitro evidence suggests that nitazoxanide does not affect the CYP450 system.^[1]

Pharmacology

Pharmacodynamics

The anti-protozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism.^[1]^[8] PFOR inhibition may also contribute to its activity against anaerobic bacteria.^[27]

It has also been shown to have activity against influenza A virus in vitro.^[28] The mechanism appears to be by selectively blocking the maturation of the viral hemagglutinin at a stage preceding resistance to endoglycosidase H digestion. This impairs hemagglutinin intracellular trafficking and insertion of the protein into the host plasma membrane.

Nitazoxanide modulates a variety of other pathways in vitro, including glutathione-S-transferase and glutamate-gated chloride ion channels in nematodes, respiration and other pathways in bacteria and cancer cells, and viral and host transcriptional factors.^[27]

Pharmacokinetics

Following oral administration, nitazoxanide is rapidly hydrolyzed to the pharmacologically active metabolite, tizoxanide, which is 99% protein bound.^[1]^[9] Tizoxanide is then glucuronide conjugated into the active metabolite, tizoxanide glucuronide.^[1] Peak plasma concentrations of the metabolites tizoxanide and tizoxanide glucuronide are observed 1–4 hours after oral administration of nitazoxanide, whereas nitazoxanide itself is not detected in blood plasma.^[1]

Roughly ²⁄₃ of an oral dose of nitazoxanide is excreted as its metabolites in feces, while the remainder of the dose excreted in urine.^[1] Tizoxanide is excreted in the urine, bile and feces.^[1] Tizoxanide glucuronide is excreted in urine and bile.^[1]

Chemistry

History

Nitazoxanide is the prototype member of the thiazolides, which is a drug class of structurally-related broad-spectrum antiparasitic compounds.^[4] Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water.

Nitazoxanide was originally discovered in the 1980s by Jean-François Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. In vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the USA were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in AIDS. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the FDA rejected an application based on uncontrolled studies.

Subsequently, Romark launched a series of controlled trials. A placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. Among malnourished children in Zambia with chronic cryptosporidiosis, a three-day course of therapy led to clinical and parasitologic improvement and improved survival. In Zambia and in a study conducted in Mexico, nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. Studies have suggested efficacy in the treatment of cyclosporiasis, isosporiasis, and amebiasis.^[29] Recent studies have also found it to be effective against beef tapeworm(Taenia saginata).^[30]

Research

Nitazoxanide is also under investigation for the treatment of COVID-19.^[31]

Pharmaceutical products

Dosage forms

Nitazoxanide is currently available in two oral dosage forms: a tablet (500 mg) and an oral suspension (100 mg per 5 ml when reconstituted).^[1]

An extended release tablet (675 mg) has been used in clinical trials for chronic hepatitis C; however, this form is not currently marketed and available for prescription.^[20]

Brand names

Nitazoxanide is sold under the brand names Adonid, Alinia, Allpar, Annita, Celectan, Colufase, Daxon, Dexidex, Diatazox, Kidonax, Mitafar, Nanazoxid, Parazoxanide, Netazox, Niazid, Nitamax, Nitax, Nitaxide, Nitaz, Nizonide, NT-TOX, Pacovanton, Paramix, Toza, and Zox.

SYN

Image result for nitazoxanide SYNTHESIS

https://www.sciencedirect.com/science/article/pii/S0960894X11002848

CLIP

Image result for nitazoxanide SYNTHESIS

CLIP

Image result for nitazoxanide SYNTHESIS

PATENT

Image result for nitazoxanide SYNTHESIS

https://patents.google.com/patent/CN105175352A/zh

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w “Nitazoxanide Prescribing Information” (PDF). Romark Pharmaceuticals. August 2013. pp. 1–5. Archived from the original (PDF) on 16 January 2016. Retrieved 3 January 2016.
^ Jump up to:^a ^b ^c ^d ^e Stockis A, Allemon AM, De Bruyn S, Gengler C (May 2002). “Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses”. Int J Clin Pharmacol Ther. 40 (5): 213–220. doi:10.5414/cpp40213. PMID 12051573.
^ “Nitazoxanide”. PubChem Compound. National Center for Biotechnology Information. Retrieved 3 January 2016.
^ Jump up to:^a ^b ^c ^d ^e Di Santo N, Ehrisman J (2013). “Research perspective: potential role of nitazoxanide in ovarian cancer treatment. Old drug, new purpose?”. Cancers (Basel). 5 (3): 1163–1176. doi:10.3390/cancers5031163. PMC 3795384. PMID 24202339. Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. … Nitazoxanide (NTZ) is a main compound of a class of broad-spectrum anti-parasitic compounds named thiazolides. It is composed of a nitrothiazole-ring and a salicylic acid moiety which are linked together by an amide bond … NTZ is generally well tolerated, and no significant adverse events have been noted in human trials [13]. … In vitro, NTZ and tizoxanide function against a wide range of organisms, including the protozoal species Blastocystis hominis, C. parvum, Entamoeba histolytica, G. lamblia and Trichomonas vaginalis [13]
^ White CA (2004). “Nitazoxanide: a new broad spectrum antiparasitic agent”. Expert Rev Anti Infect Ther. 2 (1): 43–9. doi:10.1586/14787210.2.1.43. PMID 15482170.
^ Jump up to:^a ^b ^c ^d ^e ^f Rossignol JF (October 2014). “Nitazoxanide: a first-in-class broad-spectrum antiviral agent”. Antiviral Res. 110: 94–103. doi:10.1016/j.antiviral.2014.07.014. PMID 25108173. Originally developed and commercialized as an antiprotozoal agent, nitazoxanide was later identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. … From a chemical perspective, nitazoxanide is the scaffold for a new class of drugs called thiazolides. These small-molecule drugs target host-regulated processes involved in viral replication. … A new dosage formulation of nitazoxanide is presently undergoing global Phase 3 clinical development for the treatment of influenza. Nitazoxanide inhibits a broad range of influenza A and B viruses including influenza A(pH1N1) and the avian A(H7N9) as well as viruses that are resistant to neuraminidase inhibitors. … Nitazoxanide also inhibits the replication of a broad range of other RNA and DNA viruses including respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in cell culture assays. Clinical trials have indicated a potential role for thiazolides in treating rotavirus and norovirus gastroenteritis and chronic hepatitis B and chronic hepatitis C. Ongoing and future clinical development is focused on viral respiratory infections, viral gastroenteritis and emerging infections such as dengue fever.
^ Jump up to:^a ^b Anderson, V. R.; Curran, M. P. (2007). “Nitazoxanide: A review of its use in the treatment of gastrointestinal infections”. Drugs. 67(13): 1947–1967. doi:10.2165/00003495-200767130-00015. PMID 17722965. Nitazoxanide is effective in the treatment of protozoal and helminthic infections … Nitazoxanide is a first-line choice for the treatment of illness caused by C. parvum or G. lamblia infection in immunocompetent adults and children, and is an option to be considered in the treatment of illnesses caused by other protozoa and/or helminths.
^ Jump up to:^a ^b Sisson G1, Goodwin A, Raudonikiene A, Hughes NJ, Mukhopadhyay AK, Berg DE, Hoffman PS. (July 2002). “Enzymes associated with reductive activation and action of nitazoxanide, nitrofurans, and metronidazole in Helicobacter pylori”. Antimicrob. Agents Chemother. 46 (7): 2116–23. doi:10.1128/aac.46.7.2116-2123.2002. PMC 127316. PMID 12069963. Nitazoxanide (NTZ) is a redox-active nitrothiazolyl-salicylamide
^ Jump up to:^a ^b Korba BE, Montero AB, Farrar K, et al. (January 2008). “Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication”. Antiviral Res. 77 (1): 56–63. doi:10.1016/j.antiviral.2007.08.005. PMID 17888524.
^ “Blastocystis: Resources for Health Professionals”. United States Centers for Disease Control and Prevention. 2017-05-02. Retrieved 4 January 2016.
^ Roberts T, Stark D, Harkness J, Ellis J (May 2014). “Update on the pathogenic potential and treatment options for Blastocystis sp”. Gut Pathog. 6: 17. doi:10.1186/1757-4749-6-17. PMC 4039988. PMID 24883113. Blastocystis is one of the most common intestinal protists of humans. … A recent study showed that 100% of people from low socio-economic villages in Senegal were infected with Blastocystis sp. suggesting that transmission was increased due to poor hygiene sanitation, close contact with domestic animals and livestock, and water supply directly from well and river [10]. …
Table 2: Summary of treatments and efficacy for Blastocystis infection
^ Muñoz P, Valerio M, Eworo A, Bouza E (2011). “Parasitic infections in solid-organ transplant recipients”. Curr Opin Organ Transplant. 16 (6): 565–575. doi:10.1097/MOT.0b013e32834cdbb0. PMID 22027588. Retrieved 7 January 2016. Nitazoxanide: intestinal amoebiasis: 500 mg po bid x 3 days
^ “Hymenolepiasis: Resources for Health Professionals”. United States Centers for Disease Control and Prevention. 2017-05-02. Retrieved 4 January 2016.
^ Hagel I, Giusti T (October 2010). “Ascaris lumbricoides: an overview of therapeutic targets”. Infectious Disorders – Drug Targets. 10 (5): 349–67. doi:10.2174/187152610793180876. PMID 20701574. new anthelmintic alternatives such as tribendimidine and Nitazoxanide have proved to be safe and effective against A. lumbricoides and other soil-transmitted helminthiases in human trials.
^ Shoff WH (5 October 2015). Chandrasekar PH, Talavera F, King JW (eds.). “Cyclospora Medication”. Medscape. WebMD. Retrieved 11 January 2016. Nitazoxanide, a 5-nitrothiazole derivative with broad-spectrum activity against helminths and protozoans, has been shown to be effective against C cayetanensis, with an efficacy 87% by the third dose (first, 71%; second 75%). Three percent of patients had minor side effects.
^ Li TC, Chan MC, Lee N (September 2015). “Clinical Implications of Antiviral Resistance in Influenza”. Viruses. 7 (9): 4929–4944. doi:10.3390/v7092850. PMC 4584294. PMID 26389935. Oral nitazoxanide is an available, approved antiparasitic agent (e.g., against cryptosporidium, giardia) with established safety profiles. Recently, it has been shown (together with its active metabolite tizoxanide) to possess anti-influenza activity by blocking haemagglutinin maturation/trafficking, and acting as an interferon-inducer [97]. … A large, multicenter, Phase 3 randomized-controlled trial comparing nitazoxanide, oseltamivir, and their combination in uncomplicated influenza is currently underway (NCT01610245).
Figure 1: Molecular targets and potential antiviral treatments against influenza virus infection
^ Jump up to:^a ^b Teran, C. G.; Teran-Escalera, C. N.; Villarroel, P. (2009). “Nitazoxanide vs. Probiotics for the treatment of acute rotavirus diarrhea in children: A randomized, single-blind, controlled trial in Bolivian children”. International Journal of Infectious Diseases. 13(4): 518–523. doi:10.1016/j.ijid.2008.09.014. PMID 19070525.
^ Jump up to:^a ^b Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases. 12 (1): 80–82. doi:10.1016/j.ijid.2007.04.017. PMID 17962058.
^ World Journal of Gastroenterology 2009 April 21, Emmet B Keeffe MD, Professor, Jean-François Rossignol The Romark Institute for Medical Research, Tampa
^ Jump up to:^a ^b ^c Keeffe, E. B.; Rossignol, J. F. (2009). “Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides”. World Journal of Gastroenterology. 15 (15): 1805–1808. doi:10.3748/wjg.15.1805. PMC 2670405. PMID 19370775.
^ Nikolova, Kristiana; Gluud, Christian; Grevstad, Berit; Jakobsen, Janus C (2014). “Nitazoxanide for chronic hepatitis C”. Cochrane Database of Systematic Reviews (4): CD009182. doi:10.1002/14651858.CD009182.pub2. ISSN 1465-1858. PMID 24706397.
^ “Romark Initiates Clinical Trial Of Alinia For Chronic Hepatitis C In The United States” (Press release). Medical News Today. August 16, 2007. Retrieved 2007-10-11.
^ Franciscus, Alan (October 2, 2007). “Hepatitis C Treatments in Current Clinical Development”. HCV Advocate. Archived from the original on September 6, 2003. Retrieved 2007-10-11.
^ Rossignol, Jean-François; Abu-Zekry, Mona; Hussein, Abeer; Santoro, M Gabriella (2006). “Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial”. The Lancet. 368 (9530): 124–9. CiteSeerX 10.1.1.458.1597. doi:10.1016/S0140-6736(06)68852-1. PMID 16829296.
^ Dan, M.; Sobel, J. D. (2007). “Failure of Nitazoxanide to Cure Trichomoniasis in Three Women”. Sexually Transmitted Diseases. 34 (10): 813–4. doi:10.1097/NMD.0b013e31802f5d9a. PMID 17551415.
^ “Nitazoxanide”. MedlinePlus. Retrieved 9 April 2014.
^ Jump up to:^a ^b Shakya, A; Bhat, HR; Ghosh, SK (2018). “Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent”. Current Drug Discovery Technologies. 15 (3): 201–213. doi:10.2174/1570163814666170727130003. PMID 28748751.
^ Rossignol, J. F.; La Frazia, S.; Chiappa, L.; Ciucci, A.; Santoro, M. G. (2009). “Thiazolides, a New Class of Anti-influenza Molecules Targeting Viral Hemagglutinin at the Post-translational Level”. Journal of Biological Chemistry. 284 (43): 29798–29808. doi:10.1074/jbc.M109.029470. PMC 2785610. PMID 19638339.
^ White Jr, AC (2003). “Nitazoxanide: An important advance in anti-parasitic therapy”. Am. J. Trop. Med. Hyg. 68 (4): 382–383. doi:10.4269/ajtmh.2003.68.382. PMID 12875283.
^ Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases. 12 (1): 80–2. doi:10.1016/j.ijid.2007.04.017. PMID 17962058.
^ Cynthia Liu, Qiongqiong Zhou, Yingzhu Li, Linda V. Garner, Steve P. Watkins, Linda J. Carter, Jeffrey Smoot, Anne C. Gregg, Angela D. Daniels, Susan Jervey, Dana Albaiu. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Central Science 2020; doi:10.1021/acscentsci.0c00272

External links

“Nitazoxanide”. MedlinePlus Drug Information. U.S. National Library of Medicine. 28 July 2010. Retrieved 2010-08-19.
“Parasitic infections”. Am J Transplant. 4 (Suppl 10): 142–55. 2004. doi:10.1111/j.1600-6135.2004.00677.x. PMID 15504227.

Nitazoxanide
Clinical data

Trade names	Alinia, Nizonide, and others
AHFS/Drugs.com	Monograph
MedlinePlus	a603017
License data	US FDA: Nitazoxanide
Pregnancy category	US: B (No risk in non-human studies)
Routes of administration	Oral
Drug class	Antiprotozoal Broad-spectrum antiparasitic Broad-spectrum antiviral
ATC code	P01AX11 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Protein binding	Nitazoxanide: ? Tizoxanide: over 99%^[1]^[2]
Metabolism	Rapidly hydrolyzed to tizoxanide^[1]
Metabolites	tizoxanide^[1]^[2] tizoxanide glucuronide^[1]^[2]
Elimination half-life	3.5 hours^[3]
Excretion	Renal, biliary, and fecal^[1]
Identifiers
IUPAC name [show]
CAS Number	55981-09-4
PubChem CID	41684
DrugBank	DB00507
ChemSpider	38037
UNII	SOA12P041N
KEGG	D02486
ChEMBL	ChEMBL1401
NIAID ChemDB	057131
CompTox Dashboard (EPA)	DTXSID5033757
ECHA InfoCard	100.054.465
Chemical and physical data
Formula	C₁₂H₉N₃O₅S
Molar mass	307.283 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O=C(Nc1ncc(s1)[N+]([O-])=O)c2ccccc2OC(=O)C

//////////////nitazoxanide, corona virus, covid 19

Galidesivir

March 22, 2020 4:16 am / 1 Comment on Galidesivir

ChemSpider 2D Image | Galidesivir | C11H15N5O3

Galidesivir

Molecular FormulaC₁₁H₁₅N₅O₃
Average mass265.268 Da

Immucillin-A

OLF97F86A7

UNII:OLF97F86A7

галидесивир [Russian] [INN]

غاليديسيفير [Arabic] [INN]

加利司韦 [Chinese] [INN]

Galidesivir [INN]

(2S,3S,4R,5R)-2-(4-amino- 5H-pyrrolo[3,2-d]pyrimidin- 7-yl)-5-(hydroxymethyl) pyrrolidine-3,4-diol

(2S,3S,4R,5R)-2-(4-Amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3,4-pyrrolidinediol [ACD/IUPAC Name]

10284

222631-44-9 [RN]

249503-25-1 [RN]

3,4-Pyrrolidinediol, 2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-, (2S,3S,4R,5R)- [ACD/Index Name]

BCX4430 [Wiki]

Galidesivir

249503-25-1

222631-44-9, BCX-4430 (HCL salt form of galidesivir)

2-(4-Amino-5H-pyrrolo(3,2-d)pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol.png

Galidesivir (BCX4430, Immucillin-A) is an antiviral drug, an adenosine analog^[1] (a type of nucleoside analog).^[2] It is developed by BioCryst Pharmaceuticals with funding from NIAID, originally intended as a treatment for hepatitis C, but subsequently developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease.

It also shows broad-spectrum antiviral effectiveness against a range of other RNA virus families, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses, flaviviruses and phleboviruses.^[3] BCX4430 has been demonstrated to protect against both Ebola and Marburg viruses in both rodents and monkeys, even when administered up to 48 hours after infection,^[1] and development for use in humans was then being fast-tracked due to concerns about the lack of treatment options for the 2013-2016 Ebola virus epidemic in West Africa.^[4]

BCX4430 later showed efficacy against Zika virus in a mouse model, though there are no plans for human trials at this stage.^[5]

Galidesivir is one of several antiviral drugs being tested for coronavirus disease 2019.^[6]

Image result for Galidesivir SYNTHESIS

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https://www.sciencedirect.com/science/article/pii/S0040402017305926

Image result for Galidesivir SYNTHESIS

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https://cen.acs.org/sections/coronavirus/biological-chemistry/infectious-disease/coronavirus-drug-repurposing.html

When any new virus emerges, drug and vaccine developers spring into action, searching for products to stop it in its tracks. Drug discovery campaigns launch, vaccine development efforts ramp up, and everyone mobilizes to get it all into the clinic as quickly as possible.

The current pandemic, driven by a coronavirus known as SARS-CoV-2, is no different. Already, a Phase I study of an mRNA-based vaccine developed by Moderna has begun, and major pharma companies and small biotechs are working on other types of vaccines. But even if they work, the most optimistic timelines put a vaccine a year to 18 months away.

The more immediate approach to an outbreak is to scour the medicine cabinet for existing molecules that could be repurposed against a new virus. The most advanced potential treatment is Gilead Sciences’ remdesivir, an antiviral discovered during the 2014 Ebola epidemic. The compound is already being tested in four, Phase III trials—two in China and two in the US—against the respiratory disease COVID-19. Gilead expects the first dataset from those studies to come out in April.

A new paper from CAS explored remdesivir and other possible options the cabinet might contain (ACS Cent. Sci. 2020, DOI: 10.1021/acscentsci.0c00272). CAS, a division of the American Chemical Society, which publishes C&EN, looked at the landscape of patent and journal articles covering small molecules, antibodies, and other therapeutic classes to identify therapies with potential activity against COVID-19.

SARS-CoV-2, belongs to the same family as two coronaviruses responsible for earlier outbreaks, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Because all three feature structurally similar proteins that allow entry into and replication inside host cells, CAS searched for patent data related to those more well-studied coronaviruses.

C&EN has assembled the relevant small molecules identified by CAS, which can be explored by the stage in the viral life cycle they aim to disrupt.

Patents

Patent ID	Title	Submitted Date	Granted Date
US7390890	Inhibitors of nucleoside metabolism	2007-08-23	2008-06-24
US7211653	Inhibitors of nucleoside metabolism	2005-02-03	2007-05-01
US6803455	Inhibitors of nucleoside metabolism	2003-05-22	2004-10-12
US6492347	Inhibitors of nucleoside metabolism	2002-05-23	2002-12-10
US6228847	Inhibitors of nucleoside metabolism		2001-05-08

Patent ID	Title	Submitted Date	Granted Date
EP1023308	INHIBITORS OF NUCLEOSIDE METABOLISM	2000-08-02	2005-09-07
US6066722	Inhibitors of nucleoside metabolism	2000-05-23

References

^ Jump up to:^a ^b Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, et al. (April 2014). “Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430” (PDF). Nature. 508 (7496): 402–5. Bibcode:2014Natur.508..402W. doi:10.1038/nature13027. PMID 24590073.
^ Kamat SS, Burgos ES, Raushel FM (October 2013). “Potent inhibition of the C-P lyase nucleosidase PhnI by Immucillin-A triphosphate”. Biochemistry. 52 (42): 7366–8. doi:10.1021/bi4013287. PMC 3838859. PMID 24111876.
^ Westover JB, et al. Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters. Antiviral Res. 2018 Aug;156:38-45. Westover, J. B.; Mathis, A.; Taylor, R.; Wandersee, L.; Bailey, K. W.; Sefing, E. J.; Hickerson, B. T.; Jung, K. H.; Sheridan, W. P.; Gowen, B. B. (2018). “Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters”. Antiviral Research. 156: 38–45. doi:10.1016/j.antiviral.2018.05.013. PMC 6035881. PMID 29864447.
^ Rodgers P (8 April 2014). “BioWar Lab Helping To Develop Treatment For Ebola”. Forbes Magazine.
^ Julander JG, Siddharthan V, Evans J, Taylor R, Tolbert K, Apuli C, et al. (January 2017). “Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model”. Antiviral Research. 137: 14–22. doi:10.1016/j.antiviral.2016.11.003. PMC 5215849. PMID 27838352.
^ Praveen Duddu. Coronavirus outbreak: Vaccines/drugs in the pipeline for Covid-19. clinicaltrialsarena.com 19 February 2020.

Galidesivir
Legal status

Legal status	US: Investigational New Drug
Identifiers
IUPAC name [show]
CAS Number	222631-44-9
PubChem CID	69211190
ChemSpider	8620968
UNII	OLF97F86A7
Chemical and physical data
Formula	C₁₁H₁₅N₅O₃
Molar mass	265.268 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] O[C@H]3[C@H](c2c1ncnc(N)c1[nH]c2)N[C@H](CO)[C@H]3O

//////////////Galidesivir, Immucillin-A, OLF97F86A7, UNII:OLF97F86A7, галидесивир , غاليديسيفير , 加利司韦 , BCX4430, BCX 4430, CORONAVIRUS, COVID 19

nitazoxanide

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Ranjit Desai

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

Purification

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

Purification

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

Polymorphic Data (XRPD):

References[edit]

ANALYSIS

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Keywords: Antibacterial (Antibiotics); Macrolides.

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Emory, collaborators testing antiviral drug as potential treatment for coronaviruses

Emory-discovered antiviral is poised for COVID-19 clinical trials

The nucleoside inhibitor has advantages over Gilead’s remdesivir but has yet to be tested in humans

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Medical uses

Malaria

Amebiasis

Rheumatic disease

Side effects

Pregnancy

Elderly

Drug interactions

Overdose

Pharmacology

Mechanism of action

Malaria